NM_003140.3:c.321G>T

Variant names:

• chrY-2787283-C-A
• rs2051122910
• NM_003140.3:c.321G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_003140.3(SRY):​c.321G>T​(p.Trp107Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0280
• Publications: 0 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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain 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, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRY	NM_003140.3	c.321G>T	p.Trp107Cys	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.321G>T	p.Trp107Cys	missense_variant	Exon 1 of 1	6	NM_003140.3	ENSP00000372547.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000276 AC: 1 AN: 362486 Hom.: 0 Cov.: 10 AF XY: 0.00000276 AC XY: 1 AN XY: 362486

African (AFR) AF: 0.00 AC: 0 AN: 7067

American (AMR) AF: 0.000106 AC: 1 AN: 9452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6727

East Asian (EAS) AF: 0.00 AC: 0 AN: 9481

South Asian (SAS) AF: 0.00 AC: 0 AN: 31877

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1627

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 269167

Other (OTH) AF: 0.00 AC: 0 AN: 14262

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 1 Uncertain:1

Aug 14, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of complete gonadal dysgenesis (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 107 of the SRY protein (p.Trp107Cys). The tryptophan residue is weakly conserved and there is a large physicochemical difference between tryptophan and cysteine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.7	L
PhyloP100		-0.028
PROVEAN	Uncertain	-4.1	D
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.59		Loss of MoRF binding (P = 0.0241);
MVP		0.95
MPC		1.3
ClinPred		0.97	D
GERP RS		0.64
PromoterAI		-0.048	Neutral
Varity_R		0.82
gMVP		0.90
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs2051122910; hg19: chrY-2655324;