Y-2787310-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_003140.3(SRY):c.294G>A(p.Trp98Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.68

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 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PP5: Variant Y-2787310-C-T is Pathogenic according to our data. Variant chrY-2787310-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3040170.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRY	NM_003140.3	c.294G>A	p.Trp98Ter	stop_gained	1/1	ENST00000383070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRY	ENST00000383070.2	c.294G>A	p.Trp98Ter	stop_gained	1/1		NM_003140.3	P1
XGY2	ENST00000681940.1	n.106+12571C>T		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: criteria provided, single submitter

Submissions by phenotype

SRY-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2023

The SRY c.294G>A variant is predicted to result in premature protein termination (p.Trp98*). This variant has been reported in 46,XY females with complete gonadal dysgenesis (Paliwal et al 2011. PubMed ID: 21242195; Kim A et al 2020. PubMed ID: 33060256). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in SRY are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	33
Dann	Uncertain	0.98
FATHMM_MKL	Benign	0.63	D
MutationTaster	Benign	1.0	A;D
Vest4		0.76
GERP RS		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrY-2655351;