rs104894957

Positions:

• chrY-2787426-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM5 PP3_Strong PP5_Moderate

The NM_003140.3(SRY):​c.178G>C​(p.Val60Leu) 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. V60A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 10 ACMG points.

• PM1: In a chain Sex-determining region Y protein (size 203) in uniprot entity SRY_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_003140.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant Y-2787426-C-G is Pathogenic according to our data. Variant chrY-2787426-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9739.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRY	NM_003140.3	c.178G>C	p.Val60Leu	missense_variant	1/1	ENST00000383070.2	NP_003131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRY	ENST00000383070.2	c.178G>C	p.Val60Leu	missense_variant	1/1		NM_003140.3	ENSP00000372547	P1
XGY2	ENST00000681940.1	n.106+12687C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 4

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2022

Reported in one family with several affected females with 46,XY gonadal dysgenesis, including sisters who inherited the variant from their unaffected father (Berta et al., 1990; Vilain et al., 1992); Published functional studies demonstrate V60L damages transcriptional activation and repression of target genes, subcellular localization, phosphorylation, protein stability, and Wnt/B-catenin signaling (Phillips et al., 2011; Chen et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18675318, 21849498, 1734522, 24003159, 1570829, 10690846, 2247149) -

46,XY sex reversal 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Benign	0.51	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	A;A
PROVEAN	Uncertain	-2.8	D
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.82	P
Vest4		0.58
MutPred		0.95		Loss of MoRF binding (P = 0.1063);
MVP		0.99
MPC		1.1
ClinPred		0.99	D
GERP RS		-0.84
Varity_R		0.89
gMVP		0.91

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: rs104894957; hg19: chrY-2655467;