Y-2787207-G-A

Position:

• chrY-2787207-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_003140.3(SRY):​c.397C>T​(p.Arg133Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.519

Genes affected

SRY (HGNC:11311): (sex determining region Y) This intronless gene encodes a transcription factor that is a member of the high mobility group (HMG)-box family of DNA-binding proteins. This protein is the testis-determining factor (TDF), which initiates male sex determination. Mutations in this gene give rise to XY females with gonadal dysgenesis (Swyer syndrome); translocation of part of the Y chromosome containing this gene to the X chromosome causes XX male syndrome. [provided by RefSeq, Jul 2008]

XGY2 (HGNC:34022): (XG Y-linked 2 (pseudogene))

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a mutagenesis_site Reduces nuclear localization. Strongly reduces nuclear localization; when associated with G-62. Reduces interaction with KPNB1. Does not reduce interaction with CAML. Does not abolish DNA-binding. (size 0) in uniprot entity SRY_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant Y-2787207-G-A is Pathogenic according to our data. Variant chrY-2787207-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9752.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRY	NM_003140.3	c.397C>T	p.Arg133Trp	missense_variant	1/1	ENST00000383070.2	NP_003131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRY	ENST00000383070.2	c.397C>T	p.Arg133Trp	missense_variant	1/1		NM_003140.3	ENSP00000372547	P1
XGY2	ENST00000681940.1	n.106+12468G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY sex reversal 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	A;A
PROVEAN	Pathogenic	-7.2	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.91		Loss of disorder (P = 0.0054);
MVP		0.99
MPC		1.0
ClinPred		0.99	D
GERP RS		0.64
Varity_R		0.65
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104894976; hg19: chrY-2655248;