chrX-67546320-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBS1_SupportingBS2

The NM_000044.6(AR):​c.1174C>T​(p.Pro392Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,197,127 control chromosomes in the GnomAD database, including 16 homozygotes. There are 1,564 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P392R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., 101 hem., cov: 24)
Exomes 𝑓: 0.0033 ( 15 hom. 1463 hem. )

Consequence

AR
NM_000044.6 missense

Scores

2
5
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:11

Conservation

PhyloP100: 1.64
Variant links:
Genes affected
AR (HGNC:644): (androgen receptor) The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-67546321-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1685534.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
BP4
Computational evidence support a benign effect (MetaRNN=0.0062516034).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00231 (260/112625) while in subpopulation SAS AF= 0.0278 (76/2738). AF 95% confidence interval is 0.0227. There are 1 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Hemizygotes in GnomAd4 at 101 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARNM_000044.6 linkc.1174C>T p.Pro392Ser missense_variant Exon 1 of 8 ENST00000374690.9 NP_000035.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARENST00000374690.9 linkc.1174C>T p.Pro392Ser missense_variant Exon 1 of 8 1 NM_000044.6 ENSP00000363822.3 P10275-1

Frequencies

GnomAD3 genomes
AF:
0.00230
AC:
259
AN:
112577
Hom.:
1
Cov.:
24
AF XY:
0.00288
AC XY:
100
AN XY:
34723
show subpopulations
Gnomad AFR
AF:
0.000322
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00288
Gnomad ASJ
AF:
0.00264
Gnomad EAS
AF:
0.000283
Gnomad SAS
AF:
0.0273
Gnomad FIN
AF:
0.000161
Gnomad MID
AF:
0.00837
Gnomad NFE
AF:
0.00235
Gnomad OTH
AF:
0.00463
GnomAD3 exomes
AF:
0.00448
AC:
651
AN:
145314
Hom.:
4
AF XY:
0.00680
AC XY:
305
AN XY:
44882
show subpopulations
Gnomad AFR exome
AF:
0.000112
Gnomad AMR exome
AF:
0.00181
Gnomad ASJ exome
AF:
0.00296
Gnomad EAS exome
AF:
0.0000870
Gnomad SAS exome
AF:
0.0248
Gnomad FIN exome
AF:
0.0000790
Gnomad NFE exome
AF:
0.00274
Gnomad OTH exome
AF:
0.00342
GnomAD4 exome
AF:
0.00334
AC:
3618
AN:
1084502
Hom.:
15
Cov.:
55
AF XY:
0.00414
AC XY:
1463
AN XY:
353578
show subpopulations
Gnomad4 AFR exome
AF:
0.000230
Gnomad4 AMR exome
AF:
0.00163
Gnomad4 ASJ exome
AF:
0.00230
Gnomad4 EAS exome
AF:
0.0000339
Gnomad4 SAS exome
AF:
0.0248
Gnomad4 FIN exome
AF:
0.000342
Gnomad4 NFE exome
AF:
0.00240
Gnomad4 OTH exome
AF:
0.00340
GnomAD4 genome
AF:
0.00231
AC:
260
AN:
112625
Hom.:
1
Cov.:
24
AF XY:
0.00290
AC XY:
101
AN XY:
34781
show subpopulations
Gnomad4 AFR
AF:
0.000321
Gnomad4 AMR
AF:
0.00288
Gnomad4 ASJ
AF:
0.00264
Gnomad4 EAS
AF:
0.000284
Gnomad4 SAS
AF:
0.0278
Gnomad4 FIN
AF:
0.000161
Gnomad4 NFE
AF:
0.00235
Gnomad4 OTH
AF:
0.00457
Alfa
AF:
0.00229
Hom.:
17
Bravo
AF:
0.00176
ExAC
AF:
0.00514
AC:
609

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Benign:11
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Benign:5
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The AR p.Pro392Ser variant was identified in 4 of 584 proband chromosomes (frequency: 0.00685) from a Caucasian population presenting with isolated hypospadias without micropenis or cryptorchidism, and was not identified in 690 control chromosomes from healthy individuals (Kalfa_2013_23637914). The variant was also identified in dbSNP (ID: rs201934623) as "With Pathogenic allele" and ClinVar (3 submissions with conflicting interpretations of pathogenicity: Benign(1) by Genetic Services Laboratory, University of Chicago (2016); Pathogenic(1) by UCLA Clinical Genomics Center, UCLA - CES (2014); and Uncertain significance(1) by Foundation for Research in Genetics and Endocrinology, Institute of Human Genetics (2018)). Submitters report the variant to be linked to Partial Androgen Insensitivity syndrome and Hypospadias 1, X-linked. The variant was also identified in Clinvitae, Cosmic, MutDB, and LOVD 3.0 (likely benign). The variant was identified in control databases in 684 of 166808 chromosomes (4 homozygous) at a frequency of 0.004101 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 404 of 16297 chromosomes (freq: 0.02479), Other in 16 of 4579 chromosomes (freq: 0.003494), Ashkenazi Jewish in 22 of 6922 chromosomes (freq: 0.003178), European (non-Finnish) in 189 of 71137 chromosomes (freq: 0.002657), Latino in 46 of 25450 chromosomes (freq: 0.001807), African in 5 of 14750 chromosomes (freq: 0.000339), East Asian in 1 of 12487 chromosomes (freq: 0.00008), and European (Finnish) in 1 of 15186 chromosomes (freq: 0.000066). Chakrabarty et al. identified the variant p.Pro392Ser as a somatic driver mutation in tissue samples of 18 long-standing ulcerative colitis (UC) subjects at high risk of colorectal carcinoma. (Chakrabarty_2017_28524162). The p.Pro392Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Chakrabarty, Sanjiban, et al. "Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia." British journal of cancer 117.1 (2017): 136. Kalfa, Nicolas, et al. "Minor hypospadias: the “tip of the iceberg” of the partial androgen insensitivity syndrome." PloS one 8.4 (2013): e61824. -

Aug 20, 2014
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Pathogenic
Review Status: flagged submission
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

AR: BS1, BS2 -

Androgen resistance syndrome Uncertain:1Benign:2
Feb 28, 2024
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 04, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 20, 2023
Clinical Biochemistry Laboratory, Health Services Laboratory
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG:PM1 PP3 BS1 BP2 BP4 -

Partial androgen insensitivity syndrome Pathogenic:1
Jul 01, 2014
UCLA Clinical Genomics Center, UCLA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypospadias 1, X-linked Uncertain:1
Jan 31, 2018
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The observed variant c.1174C>T (p.P392S) has the minor allele frequency of 0.74% in 1000 Genomes and 0.8% in ExAC databases. The in silico predictions of the variant is polymorphism by Mutation Taster, benign by PolyPhen and damaging by SIFT. -

not specified Benign:1
Sep 22, 2016
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1
Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

AR-related disorder Benign:1
Jul 02, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Androgen resistance syndrome;C0268301:Partial androgen insensitivity syndrome Benign:1
Feb 21, 2022
Pars Genome Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.0092
T
BayesDel_noAF
Pathogenic
0.23
CADD
Benign
16
DANN
Uncertain
1.0
DEOGEN2
Benign
0.029
T;.;.;.;T;.
FATHMM_MKL
Benign
0.74
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D
MetaRNN
Benign
0.0063
T;T;T;T;T;T
MetaSVM
Uncertain
0.65
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-2.2
.;N;D;D;.;.
REVEL
Pathogenic
0.77
Sift
Uncertain
0.023
.;D;T;D;.;.
Sift4G
Benign
0.11
T;T;T;T;T;T
Vest4
0.071
MVP
0.98
MPC
0.49
ClinPred
0.017
T
GERP RS
3.3
Varity_R
0.091
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201934623; hg19: chrX-66766162; COSMIC: COSV65955899; API