Y-2787321-C-T

Variant names:

• chrY-2787321-C-T
• NM_003140.3:c.283G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM5 PP3_Strong

The NM_003140.3(SRY):​c.283G>A​(p.Gly95Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G95E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_003140.3 (SRY) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 9750
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_003140.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrY-2787320-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9755.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRY	NM_003140.3	c.283G>A	p.Gly95Arg	missense_variant	Exon 1 of 1	ENST00000383070.2	NP_003131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRY	ENST00000383070.2	c.283G>A	p.Gly95Arg	missense_variant	Exon 1 of 1	6	NM_003140.3	ENSP00000372547.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PROVEAN	Pathogenic	-7.9	D
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.98		Gain of disorder (P = 0.0284);
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		-1.3
Varity_R		0.96
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrY-2655362;