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X-67723746-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_000044.6(AR):c.2668G>T(p.Val890Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V890M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 21)

Consequence

AR
NM_000044.6 missense

Scores

7
4
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.76
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 Pathogenic. Variant got 14 ACMG points.

PS1
Transcript NM_000044.6 (AR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 430163
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000044.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-67723746-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 279690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.848
PP5
Variant X-67723746-G-T is Pathogenic according to our data. Variant chrX-67723746-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1338633.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ARNM_000044.6 linkuse as main transcriptc.2668G>T p.Val890Leu missense_variant 8/8 ENST00000374690.9
ARNM_001011645.3 linkuse as main transcriptc.1072G>T p.Val358Leu missense_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ARENST00000374690.9 linkuse as main transcriptc.2668G>T p.Val890Leu missense_variant 8/81 NM_000044.6 P1P10275-1
ARENST00000396044.8 linkuse as main transcriptc.*29G>T 3_prime_UTR_variant 5/51
ARENST00000396043.4 linkuse as main transcriptc.*1016G>T 3_prime_UTR_variant, NMD_transcript_variant 9/91
ARENST00000612452.5 linkuse as main transcriptc.2668G>T p.Val890Leu missense_variant, NMD_transcript_variant 8/95 P10275-1

Frequencies

GnomAD3 genomes
Cov.:
21
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
21

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 24, 2021DNA sequence analysis of the AR gene demonstrated a sequence change, c.2668G>T, in exon 8 that results in an amino acid change, p.Val890Leu. This sequence change is absent from known population databases (gnomAD). The p.Val890Leu change affects a highly conserved amino acid residue located in a domain of the AR protein that is known to be functional. The p.Val890Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular sequence change (reported as p.Val889Leu) has been previously reported in individuals with AR-related disorders of sexual development (PMID: 20150575). A different pathogenic sequence change affecting the same amino acid residue (p.Val890Met, reported as p.Val889Met)) has also been described in individuals with AR-related disorders (PMID: 10425033). The p.Val890Leu amino acid change occurs in a region of the AR gene where other missense sequence changes have been described in patients with AR-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.69
D
BayesDel_noAF
Pathogenic
0.76
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Benign
0.10
T;.;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.85
D;D;D
MetaSVM
Pathogenic
0.98
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.76
T
Sift4G
Uncertain
0.0040
D;D;D
Vest4
0.80
MVP
1.0
MPC
1.2
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.94
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-66943588; API