Y-2787334-G-C

Variant names:

• chrY-2787334-G-C
• rs104894959
• NM_003140.3:c.270C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PP2 PP3_Strong PP5

The NM_003140.3(SRY):​c.270C>G​(p.Ile90Met) 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).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.20
• Publications: 8 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: Likely_pathogenic. The variant received 8 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, 5 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, 0.994
• PP5: Variant Y-2787334-G-C is Pathogenic according to our data. Variant chrY-2787334-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9741.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003140.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRY	NM_003140.3	MANE Select	c.270C>G	p.Ile90Met	missense	Exon 1 of 1	NP_003131.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRY	ENST00000383070.2	TSL:6 MANE Select	c.270C>G	p.Ile90Met	missense	Exon 1 of 1	ENSP00000372547.1
	XGY2	ENST00000679825.1		n.446G>C		non_coding_transcript_exon	Exon 4 of 4
	XGY2	ENST00000679518.1		n.106+12595G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000148 AC: 1 AN: 67342 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000550 AC: 2 AN: 363377 Hom.: 0 Cov.: 1 AF XY: 0.00000550 AC XY: 2 AN XY: 363377

African (AFR) AF: 0.00 AC: 0 AN: 7076

American (AMR) AF: 0.00 AC: 0 AN: 9506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6744

East Asian (EAS) AF: 0.00 AC: 0 AN: 9490

South Asian (SAS) AF: 0.00 AC: 0 AN: 32077

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1629

European-Non Finnish (NFE) AF: 0.00000741 AC: 2 AN: 269733

Other (OTH) AF: 0.00 AC: 0 AN: 14294

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

46,XY TRUE HERMAPHRODITISM Pathogenic:1

Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

46,XY sex reversal 1 Pathogenic:1

Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.65
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		4.2
PROVEAN	Uncertain	-3.0	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.97		Gain of disorder (P = 0.011)
MVP		1.0
MPC		1.1
ClinPred		0.97	D
GERP RS		0.64
PromoterAI		-0.013	Neutral
Varity_R		0.93
gMVP		0.97
Mutation Taster		=56/44	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: rs104894959; hg19: chrY-2655375;