rs1057519627

Variant names:

• chrY-2787377-C-A
• rs1057519627
• NM_003140.3:c.227G>T

Your query was ambiguous. Multiple possible variants found:

• chrY-2787377-C-A
• chrY-2787377-C-G
• chrY-2787377-C-T

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.227G>T​(p.Arg76Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.07

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 mutagenesis_site Reduces nuclear localization. Reduces DNA-binding. Does not reduce interaction with KPNB1 and CAML. Does not affectnuclear import. (size 0) in uniprot entity SRY_HUMAN
• 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, 0.966
• PP5: Variant Y-2787377-C-A is Pathogenic according to our data. Variant chrY-2787377-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393470.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.227G>T	p.Arg76Leu	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.227G>T	p.Arg76Leu	missense_variant	Exon 1 of 1	6	NM_003140.3	ENSP00000372547.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 1 Pathogenic:1

Jan 26, 2017

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Benign	0.51	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PROVEAN	Pathogenic	-6.6	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.77		Loss of disorder (P = 0.026);
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		-0.84
Varity_R		0.91
gMVP		0.95

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: rs1057519627; hg19: chrY-2655418;