Y-2787224-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 PP3 PP5_Moderate

The NM_003140.3(SRY):c.380A>G(p.Tyr127Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y127F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.73

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 chain Sex-determining region Y protein (size 203) in uniprot entity SRY_HUMAN there are 33 pathogenic changes around while only 0 benign (100%) in NM_003140.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrY-2787224-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 9756.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant Y-2787224-T-C is Pathogenic according to our data. Variant chrY-2787224-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 470196.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.380A>G	p.Tyr127Cys	missense_variant	1/1	ENST00000383070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRY	ENST00000383070.2	c.380A>G	p.Tyr127Cys	missense_variant	1/1		NM_003140.3	P1
XGY2	ENST00000681940.1	n.106+12485T>C		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

46,XY sex reversal 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2019

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the p.Tyr127 amino acid residue in SRY have been observed in affected individuals (PMID: 12107262, 28787711). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change disrupts the ability of SRY to accumulate in the nucleus and bind to DNA in cell culture, but does not affect its interaction with calmodulin (PMID: 12409269, 20528776). This variant has been observed to be de novo in an individual affected with 46,XY disorder of sexual development (46,XY DSD) (Invitae) and has also been reported in the literature in an additional individual affected with 46, XY DSD (PMID: 8019555). ClinVar contains an entry for this variant (Variation ID: 470196). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 127 of the SRY protein (p.Tyr127Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	28
Dann	Benign	0.95
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D;D
PROVEAN	Pathogenic	-8.5	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.96		Loss of phosphorylation at Y127 (P = 0.0474);
MVP		1.0
MPC		1.2
ClinPred		0.95	D
GERP RS		0.64
Varity_R		0.95
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894973; hg19: chrY-2655265;