Y-2787015-G-T

Position:

• chrY-2787015-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_003140.3(SRY):​c.589C>A​(p.Arg197Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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_benign. Variant got -3 ACMG points.

• PM1: In a chain Sex-determining region Y protein (size 203) in uniprot entity SRY_HUMAN there are 34 pathogenic changes around while only 1 benign (97%) in NM_003140.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.3544641).
• BS2: High Hemizygotes in GnomAdExome4 at 2 YL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRY	NM_003140.3	c.589C>A	p.Arg197Ser	missense_variant	1/1	ENST00000383070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRY	ENST00000383070.2	c.589C>A	p.Arg197Ser	missense_variant	1/1		NM_003140.3	P1
XGY2	ENST00000681940.1	n.106+12276G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000550 AC: 2 AN: 363468 Hom.: 0 Cov.: 0 AF XY: 0.00000550 AC XY: 2 AN XY: 363468

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000741

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2023

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SRY-related conditions. ClinVar contains an entry for this variant (Variation ID: 1505389). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 197 of the SRY protein (p.Arg197Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.098	T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Benign	0.35	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.75	N
PROVEAN	Benign	-0.38	N
Sift	Benign	0.077	T
Sift4G	Benign	0.41	T
Polyphen		0.14	B
Vest4		0.20
MVP		0.98
MPC		0.48
ClinPred		0.12	T
GERP RS		-1.3
Varity_R		0.20
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs756606002; hg19: chrY-2655056;