chrX-67717526-C-T

Variant names:

• chrX-67717526-C-T
• rs137852601
• NM_000044.6:c.2222C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000044.6(AR):​c.2222C>T​(p.Ser741Phe) variant causes a missense change. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S741C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.10
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• androgen insensitivity syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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-67717526-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9860.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 147 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 1.2272 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to androgen insensitivity syndrome, Kennedy disease, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant X-67717526-C-T is Pathogenic according to our data. Variant chrX-67717526-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 988302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2222C>T	p.Ser741Phe	missense_variant	Exon 5 of 8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.626C>T	p.Ser209Phe	missense_variant	Exon 6 of 9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2222C>T	p.Ser741Phe	missense_variant	Exon 5 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Mar 29, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Androgen resistance syndrome Pathogenic:1

Jul 04, 2024

Genetics Department, Polish Mother's Memorial Hospital Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The patient is a 59-year-old phenotypically female with 46,XY karyotype, and typical symptoms of complete androgen insensitivity syndrome. The detected NM_000044.6:c.2222C>T p.(Ser741Phe) variant causes a missense change. The variant was absent in control chromosomes in populational databases. The in-silico tools predicted a pathogenic outcome for this variant. The variant has been reported in ClinVar as likely pathogenic and in LOVD as pathogenic. Another variant affecting the same amino acid position but resulting in a different missense (i.e., Ser741Cys) has been classified as pathogenic in ClinVar. The variant is localized in the hotspot region in the window of +/- 8 amino acids, where ten missense changes were described as pathogenic, three as uncertain, and none as benign or likely benign. The variant was classified as pathogenic with 10 ACMG points (criteria: PS4_moderate, PM1, PM2, PM5, PP3, PP4). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		6.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.3	.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.88
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.99
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852601; hg19: chrX-66937368; COSMIC: COSV65953576;