rs104894971

Variant names:

• chrY-2787551-C-T
• rs104894971
• NM_003140.3:c.53G>A

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.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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.675
• Publications: 11 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 chain Sex-determining region Y protein (size 203) in uniprot entity SRY_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) 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,XY complete gonadal dysgenesis, 46,XY sex reversal 1, 46,XX sex reversal 1, 46,XY partial gonadal dysgenesis, 46,XX ovotesticular disorder of sex development.
• 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 VariationId is 9754.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRY	NM_003140.3	MANE Select	c.53G>A	p.Ser18Asn	missense	Exon 1 of 1	NP_003131.1	A7WPU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRY	ENST00000383070.2	TSL:6 MANE Select	c.53G>A	p.Ser18Asn	missense	Exon 1 of 1	ENSP00000372547.1	Q05066
	XGY2	ENST00000679825.1		n.663C>T		non_coding_transcript_exon	Exon 4 of 4
	XGY2	ENST00000680845.1		n.237C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 33667 Hom.: 0 Cov.: 0

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: 3 AN: 67792 AF XY: 0.0000443

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: 4 AN: 363072 Hom.: 0 Cov.: 15 AF XY: 0.0000110 AC XY: 4 AN XY: 363072

African (AFR) AF: 0.00 AC: 0 AN: 7071

American (AMR) AF: 0.000315 AC: 3 AN: 9514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6741

East Asian (EAS) AF: 0.00 AC: 0 AN: 9492

South Asian (SAS) AF: 0.00 AC: 0 AN: 32095

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1630

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 269377

Other (OTH) AF: 0.0000701 AC: 1 AN: 14272

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 33667 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 33667

African (AFR) AF: 0.00 AC: 0 AN: 8604

American (AMR) AF: 0.00 AC: 0 AN: 3663

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 776

East Asian (EAS) AF: 0.00 AC: 0 AN: 1301

South Asian (SAS) AF: 0.00 AC: 0 AN: 1514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3407

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 13652

Other (OTH) AF: 0.00 AC: 0 AN: 463

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000867 AC: 6

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	46,XY sex reversal 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.75
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.68
PROVEAN	Benign	-0.63	N
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.66
MutPred		0.78		Loss of phosphorylation at S18 (P = 0.0666)
MVP		0.92
MPC		0.32
ClinPred		0.031	T
GERP RS		-1.3
PromoterAI		-0.0036	Neutral
Varity_R		0.24
gMVP		0.81
Mutation Taster		=93/7	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: rs104894971; hg19: chrY-2655592;