Y-2787283-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_003140.3(SRY):c.321G>T(p.Trp107Cys) 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0280

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_003140.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRY	NM_003140.3	c.321G>T	p.Trp107Cys	missense_variant	1/1	ENST00000383070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRY	ENST00000383070.2	c.321G>T	p.Trp107Cys	missense_variant	1/1		NM_003140.3	P1
XGY2	ENST00000681940.1	n.106+12544C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000276 AC: 1 AN: 362486 Hom.: 0 Cov.: 10 AF XY: 0.00000276 AC XY: 1 AN XY: 362486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000106

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: 0.00

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

Invitae

Aug 14, 2020

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of complete gonadal dysgenesis (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 107 of the SRY protein (p.Trp107Cys). The tryptophan residue is weakly conserved and there is a large physicochemical difference between tryptophan and cysteine. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-4.1	D
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.59		Loss of MoRF binding (P = 0.0241);
MVP		0.95
MPC		1.3
ClinPred		0.97	D
GERP RS		0.64
Varity_R		0.82
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs2051122910; hg19: chrY-2655324;