rs104894969

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrY-2787412-C-T
• chrY-2787412-C-G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV005839617: Experimental studies have shown that this missense change affects SRY function (PMID:7813448, 16762365).".

• 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005839617: Experimental studies have shown that this missense change affects SRY function (PMID: 7813448, 16762365).
• PM1: In a hotspot region, there are 6 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,XY complete gonadal dysgenesis, 46,XY sex reversal 1, 46,XX sex reversal 1, 46,XY partial gonadal dysgenesis, 46,XX ovotesticular disorder of sex development.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003140.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRY	NM_003140.3	MANE Select	c.192G>A	p.Met64Ile	missense	Exon 1 of 1	NP_003131.1	A7WPU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRY	ENST00000383070.2	TSL:6 MANE Select	c.192G>A	p.Met64Ile	missense	Exon 1 of 1	ENSP00000372547.1	Q05066
	XGY2	ENST00000679825.1		n.524C>T		non_coding_transcript_exon	Exon 4 of 4
	XGY2	ENST00000679518.1		n.106+12673C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	46,XY sex reversal 1 (2)

Computational scores

Source: dbNSFP v4.9

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
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		0.027	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;