Y-2787258-A-T

Variant names:

• chrY-2787258-A-T
• NM_003140.3:c.346T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_003140.3(SRY):​c.346T>A​(p.Leu116Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a DNA_binding_region HMG box (size 68) in uniprot entity SRY_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_003140.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRY	NM_003140.3	c.346T>A	p.Leu116Ile	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.346T>A	p.Leu116Ile	missense_variant	Exon 1 of 1	6	NM_003140.3	ENSP00000372547.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 8

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	2.0	M
PROVEAN	Benign	-2.0	N
Sift	Benign	0.034	D
Sift4G	Uncertain	0.018	D
Polyphen		0.73	P
Vest4		0.43
MutPred		0.71		Gain of methylation at K115 (P = 0.0861);
MVP		0.96
MPC		1.1
ClinPred		0.91	D
GERP RS		-1.3
Varity_R		0.48
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrY-2655299;