X-67545306-T-TTGC

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4_SupportingPP5BS2

The NM_000044.6(AR):c.170_172dup(p.Leu57dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,143,668 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 5 hem., cov: 19)

Exomes 𝑓: 0.000017 ( 0 hom. 4 hem. )

Consequence

AR
NM_000044.6 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 2.29

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]

AR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000044.6. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant X-67545306-T-TTGC is Pathogenic according to our data. Variant chrX-67545306-T-TTGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 958035.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

BS2

High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6 linkuse as main transcript	c.170_172dup	p.Leu57dup	inframe_insertion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9 linkuse as main transcript	c.170_172dup	p.Leu57dup	inframe_insertion	1/8	1	NM_000044.6	P1	P10275-1

Frequencies

GnomAD3 genomes

AF:

0.000121

AC:

AN:

82407

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

17137

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00539

Gnomad AMR

AF:

0.000290

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000121

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000189

AC:

AN:

158966

Hom.:

AF XY:

0.0000347

AC XY:

AN XY:

57580

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000417

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000170

AC:

AN:

1061261

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

343641

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000133

Gnomad4 NFE exome

AF:

0.0000134

Gnomad4 OTH exome

AF:

0.0000228

GnomAD4 genome

AF:

0.000121

AC:

AN:

82407

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

AN XY:

17137

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000290

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000121

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This variant, c.170_172dup, results in the insertion of 1 amino acid(s) of the AR protein (p.Leu57dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752055010, gnomAD 0.007%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with AR-related conditions (PMID: 25500996, 28261839; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as p.Leu57dup and p.57_58insLeu. ClinVar contains an entry for this variant (Variation ID: 958035). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Malignant tumor of prostate

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2023

The c.170_172dupTGC (p.L57dup) alteration, located in coding exon 1 of the AR gene. The alteration consists of an in-frame duplication of 3 nucleotides from position 170 to 172. This results in the duplication of a leucine residue at codon 57._x000D_ _x000D_ for AR-related androgen insensitivity syndrome; however, it is unlikely to be causative of AR-related spinal and bulbar muscular atrophy. Based on data from gnomAD, the c.170_172dupTGC allele has an overall frequency of 0.003% (6/174505) total alleles studied, with 2 hemizygotes observed. The highest observed frequency was 0.007% (1/14938) of African alleles. This variant has been reported in multiple individuals with features consistent with AR-related androgen insensitivity syndrome (Ferlin, 2006; Su, 2017; Liu, 2020), including a de novo occurrence (He, 2021). A functional study has demonstrated reduced cellular expression and transactivation activity in a luciferase assay (70% of wildtype) for p.L57dup (Tadokoro-Cuccaro, 2014). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over