X-67717484-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1 PP3 BP4_Strong BS2

The NM_000044.6(AR):c.2180G>T(p.Arg727Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000415 in 1,210,163 control chromosomes in the GnomAD database, including 3 homozygotes. There are 169 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. R727C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., 29 hem., cov: 24)
  • Exomes 𝑓: 0.00040 (3 hom. 140 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:1
• Conservation: PhyloP100: 10.0

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000044.6
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.021373868).
• BS2: High Hemizygotes in GnomAd at 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2180G>T	p.Arg727Leu	missense_variant	5/8	ENST00000374690.9
AR	NM_001011645.3	c.584G>T	p.Arg195Leu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2180G>T	p.Arg727Leu	missense_variant	5/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.2173+5795G>T		intron_variant		1
AR	ENST00000396043.4	c.*528G>T		3_prime_UTR_variant, NMD_transcript_variant	6/9	1
AR	ENST00000612452.5	c.2180G>T	p.Arg727Leu	missense_variant, NMD_transcript_variant	5/9	5

Frequencies

GnomAD3 genomes AF: 0.000517 AC: 58 AN: 112216 Hom.: 0 Cov.: 24 AF XY: 0.000844 AC XY: 29 AN XY: 34374

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.000659

GnomAD3 exomes AF: 0.000909 AC: 166 AN: 182614 Hom.: 2 AF XY: 0.000848 AC XY: 57 AN XY: 67216

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: 0.00835

Gnomad NFE exome AF: 0.000270

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000404 AC: 444 AN: 1097895 Hom.: 3 Cov.: 32 AF XY: 0.000385 AC XY: 140 AN XY: 363317

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00827

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.000456

GnomAD4 genome AF: 0.000517 AC: 58 AN: 112268 Hom.: 0 Cov.: 24 AF XY: 0.000842 AC XY: 29 AN XY: 34436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00781

Gnomad4 NFE AF: 0.000169

Gnomad4 OTH AF: 0.000651

Alfa AF: 0.000166 Hom.: 7

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Prostate cancer susceptibility Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2000

- -

Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.74
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.93
MVP		1.0
MPC		1.4
ClinPred		0.20	T
GERP RS		5.0
Varity_R		0.98
gMVP		0.98

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: rs137852593; hg19: chrX-66937326; COSMIC: COSV65953933;