X-67717480-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000044.6(AR):c.2176T>C(p.Phe726Leu) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: AR NM_000044.6 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000044.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant X-67717480-T-C is Pathogenic according to our data. Variant chrX-67717480-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 458362.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67717480-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2176T>C	p.Phe726Leu	missense_variant, splice_region_variant	5/8	ENST00000374690.9
AR	NM_001011645.3	c.580T>C	p.Phe194Leu	missense_variant, splice_region_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2176T>C	p.Phe726Leu	missense_variant, splice_region_variant	5/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.2173+5791T>C		intron_variant		1
AR	ENST00000396043.4	c.*524T>C		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/9	1
AR	ENST00000612452.5	c.2176T>C	p.Phe726Leu	missense_variant, splice_region_variant, NMD_transcript_variant	5/9	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2017

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense disrupts AR intra- and inter-molecular interactions, and decreases its transcriptional activation activity in cell culture (PMID: 11376111, 15541764, 16365032). This variant has been reported in individuals affected with partial androgen insensitivity syndrome and/or ambiguous genitalia (PMID: 7671849, 10092153, Invitae). This variant is also known as F725L in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 726 of the AR protein (p.Phe726Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.98
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.99

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: rs1555996810; hg19: chrX-66937322;