rs756606002

Variant names:

• chrY-2787015-G-A
• rs756606002
• NM_003140.3:c.589C>T

Your query was ambiguous. Multiple possible variants found:

• chrY-2787015-G-A
• chrY-2787015-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_003140.3(SRY):​c.589C>T​(p.Arg197Cys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R197S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000030 (0 hom., 1 hem., cov: 0)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03
• 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: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25749803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRY	NM_003140.3	c.589C>T	p.Arg197Cys	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.589C>T	p.Arg197Cys	missense_variant	Exon 1 of 1	6	NM_003140.3	ENSP00000372547.1

Frequencies

GnomAD3 genomes AF: 0.0000303 AC: 1 AN: 33055 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000278

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: 0.0000295 AC: 2 AN: 67692 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000550 AC: 2 AN: 363468 Hom.: 0 Cov.: 0 AF XY: 0.00000550 AC XY: 2 AN XY: 363468

African (AFR) AF: 0.00 AC: 0 AN: 7077

American (AMR) AF: 0.000210 AC: 2 AN: 9513

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6748

East Asian (EAS) AF: 0.00 AC: 0 AN: 9493

South Asian (SAS) AF: 0.00 AC: 0 AN: 32081

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12883

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 269760

Other (OTH) AF: 0.00 AC: 0 AN: 14287

GnomAD4 genome AF: 0.0000303 AC: 1 AN: 33055 Hom.: 0 Cov.: 0 AF XY: 0.0000303 AC XY: 1 AN XY: 33055

African (AFR) AF: 0.00 AC: 0 AN: 8410

American (AMR) AF: 0.000278 AC: 1 AN: 3597

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 766

East Asian (EAS) AF: 0.00 AC: 0 AN: 1260

South Asian (SAS) AF: 0.00 AC: 0 AN: 1452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 75

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 13501

Other (OTH) AF: 0.00 AC: 0 AN: 460

ExAC AF: 0.0000288 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Benign	0.26	T
MutationAssessor	Benign	0.60	N
PhyloP100		5.0
PROVEAN	Benign	-0.81	N
Sift	Benign	0.16	T
Sift4G	Benign	0.27	T
Polyphen		0.0030	B
Vest4		0.16
MVP		0.96
MPC		0.47
ClinPred		0.071	T
GERP RS		-1.3
Varity_R		0.13
gMVP		0.12
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756606002; hg19: chrY-2655056;