NM_003140.3:c.192G>A

Variant names:

• chrY-2787412-C-T
• rs104894969
• NM_003140.3:c.192G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PP2 PP3_Strong PP5_Moderate

The NM_003140.3(SRY):​c.192G>A​(p.Met64Ile) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.68
• Publications: 8 publications found

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_003140.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.13831 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XX sex reversal 1, 46,XY sex reversal 1, 46,XY partial gonadal dysgenesis, 46,XX ovotesticular disorder of sex development, 46,XY complete gonadal dysgenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant Y-2787412-C-T is Pathogenic according to our data. Variant chrY-2787412-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 9747.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRY	NM_003140.3	c.192G>A	p.Met64Ile	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.192G>A	p.Met64Ile	missense_variant	Exon 1 of 1	6	NM_003140.3	ENSP00000372547.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 1 Pathogenic:2

Nov 29, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 64 of the SRY protein (p.Met64Ile). 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 missense change has been observed in individual(s) with 46,XY differences of sex development (PMID: 2247149, 37147882). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 9747). 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 disruptive. Experimental studies have shown that this missense change affects SRY function (PMID: 7813448, 16762365). This variant disrupts the p.Met64 amino acid residue in SRY. Other variant(s) that disrupt this residue have been observed in individuals with SRY-related conditions (PMID: 9678356), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.7
PROVEAN	Uncertain	-3.6	D
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Vest4		0.75
ClinPred		0.97	D
GERP RS		0.64
PromoterAI		0.027	Neutral
Varity_R		0.66
gMVP		0.91
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs104894969; hg19: chrY-2655453;