rs104894971

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PP2PP3_StrongPP5

The NM_003140.3(SRY):c.53G>A(p.Ser18Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 0)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Failed GnomAD Quality Control

Consequence

SRY
NM_003140.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.675

Publications

11 publications found

Variant links:

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]

SRY links:

XGY2 (HGNC:34022): (XG Y-linked 2 (pseudogene))

XGY2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a chain Sex-determining region Y protein (size 203) in uniprot entity SRY_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) 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,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, 0.987

PP5

Variant Y-2787551-C-T is Pathogenic according to our data. Variant chrY-2787551-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9754.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 link	c.53G>A	p.Ser18Asn	missense_variant	Exon 1 of 1	ENST00000383070.2	NP_003131.1	Q05066A7WPU8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRY	ENST00000383070.2 link	c.53G>A	p.Ser18Asn	missense_variant	Exon 1 of 1	6	NM_003140.3	ENSP00000372547.1		Q05066

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

33667

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000443

AC:

AN:

67792

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000140

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000316

Gnomad OTH exome

AF:

0.000624

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000110

AC:

AN:

363072

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

7071

American (AMR)

AF:

0.000315

AC:

AN:

9514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6741

East Asian (EAS)

AF:

0.00

AC:

AN:

9492

South Asian (SAS)

AF:

0.00

AC:

AN:

32095

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1630

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

269377

Other (OTH)

AF:

0.0000701

AC:

AN:

14272

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

33667

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33667

African (AFR)

AF:

0.00

AC:

AN:

8604

American (AMR)

AF:

0.00

AC:

AN:

3663

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

776

East Asian (EAS)

AF:

0.00

AC:

AN:

1301

South Asian (SAS)

AF:

0.00

AC:

AN:

1514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3407

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

13652

Other (OTH)

AF:

0.00

AC:

AN:

463

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000867

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

46,XY sex reversal 1

Pathogenic:1

May 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.73

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.2

PhyloP100

0.68

PROVEAN

Benign

-0.63

Sift

Benign

0.12

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.66

MutPred

0.78

Loss of phosphorylation at S18 (P = 0.0666);

MVP

0.92

MPC

0.32

ClinPred

0.031

GERP RS

-1.3

PromoterAI

-0.0036

Neutral

(source)

Varity_R

0.24

gMVP

0.81

Mutation Taster

=93/7

disease causing (ClinVar)

(source)

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

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rs104894971

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over