NM_003140.3:c.380A>T

Variant names:

• chrY-2787224-T-A
• rs104894973
• NM_003140.3:c.380A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM5 PP2 PP3_Strong PP5

The NM_003140.3(SRY):​c.380A>T​(p.Tyr127Phe) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y127C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.73
• Publications: 12 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 10 ACMG points.

• PM1: In a region_of_interest Sufficient for interaction with KPNB1 (size 77) in uniprot entity SRY_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_003140.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrY-2787224-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 470196.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.991
• PP5: Variant Y-2787224-T-A is Pathogenic according to our data. Variant chrY-2787224-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 9756.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRY	NM_003140.3	c.380A>T	p.Tyr127Phe	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.380A>T	p.Tyr127Phe	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY sex reversal 1 Pathogenic:1

Jul 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.7
PROVEAN	Uncertain	-3.8	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.95		Loss of phosphorylation at Y127 (P = 0.0474);
MVP		0.99
MPC		1.1
ClinPred		0.97	D
GERP RS		0.64
PromoterAI		-0.019	Neutral
Varity_R		0.79
gMVP		0.97
Mutation Taster		=2/98	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: rs104894973; hg19: chrY-2655265;