rs104894969

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrY-2787412-C-G
• chrY-2787412-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1 PM1 PP2 PP3_Strong

The NM_003140.3(SRY):​c.192G>C​(p.Met64Ile) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_003140.3 (SRY) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRY	NM_003140.3	c.192G>C	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>C	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

ClinVar

Not reported in ClinVar

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	0.69	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
Polyphen		0.90	P
Vest4		0.75
MutPred		0.94		Loss of disorder (P = 0.0506);
MVP		1.0
MPC		1.1
ClinPred		0.97	D
GERP RS		0.64
PromoterAI		0.024	Neutral
Varity_R		0.66
gMVP		0.91
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs104894969; hg19: chrY-2655453; COSMIC: COSV106545379; COSMIC: COSV106545379;