X-67545265-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_000044.6(AR):c.119G>A(p.Arg40Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,097,582 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.000017 (0 hom. 7 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33673233).
• BP6: Variant X-67545265-G-A is Benign according to our data. Variant chrX-67545265-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2946522.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67545265-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.119G>A	p.Arg40Lys	missense_variant	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.119G>A	p.Arg40Lys	missense_variant	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.0000220 AC: 4 AN: 182144 Hom.: 0 AF XY: 0.0000298 AC XY: 2 AN XY: 67048

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000732

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: 0.0000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 19 AN: 1097582 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 363010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000854

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 20

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	20
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.97	N;N;N;.;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0070	D;D;D;.;.
Sift4G	Benign	0.19	T;T;T;T;T
Vest4		0.12
MVP		0.96
MPC		0.51
ClinPred		0.21	T
GERP RS		4.5
Varity_R		0.23
gMVP		0.70

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

Other links and lift over

dbSNP: rs147842041; hg19: chrX-66765107;