chrY-2787592-A-T

Variant names:

• chrY-2787592-A-T
• rs104894975
• NM_003140.3:c.12T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_003140.3(SRY):​c.12T>A​(p.Tyr4*) variant causes a stop gained 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0520
• Publications: 1 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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 38 pathogenic variants in the truncated region.
• PP5: Variant Y-2787592-A-T is Pathogenic according to our data. Variant chrY-2787592-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9751.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRY	NM_003140.3	MANE Select	c.12T>A	p.Tyr4*	stop_gained	Exon 1 of 1	NP_003131.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRY	ENST00000383070.2	TSL:6 MANE Select	c.12T>A	p.Tyr4*	stop_gained	Exon 1 of 1	ENSP00000372547.1
	XGY2	ENST00000680845.1		n.278A>T		non_coding_transcript_exon	Exon 5 of 5
	XGY2	ENST00000679518.1		n.106+12853A>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 13

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY sex reversal 1 Pathogenic:1

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	22
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.16	N
PhyloP100		0.052
Vest4		0.53
PromoterAI		-0.0053	Neutral
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs104894975; hg19: chrY-2655633;