rs104894968

Variant names:

• chrY-2787401-A-G
• rs104894968
• NM_003140.3:c.203T>C
• SRY p.Ile68Thr

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PP2 PP3_Strong PP5_Moderate

The NM_003140.3(SRY):​c.203T>C​(p.Ile68Thr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000825911: Experimental studies have shown that this missense change exhibits a significant reduction in sequence-specific DNA recognition (PMID:7718558), shows no binding activity compared to wild type, and fails to induce activation of a male-specific development pathway in vitro (PMID:7985018).".

• Frequency: Genomes: not found (cov: 0)
• Consequence: SRY NM_003140.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.63
• Publications: 3 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000825911: Experimental studies have shown that this missense change exhibits a significant reduction in sequence-specific DNA recognition (PMID: 7718558), shows no binding activity compared to wild type, and fails to induce activation of a male-specific development pathway in vitro (PMID: 7985018).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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,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, 0.991
• PP5: Variant Y-2787401-A-G is Pathogenic according to our data. Variant chrY-2787401-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9746.Status of the report is criteria_provided_single_submitter, 1 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.203T>C	p.Ile68Thr	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.203T>C	p.Ile68Thr	missense	Exon 1 of 1	ENSP00000372547.1	Q05066
	XGY2	ENST00000679825.1		n.513A>G		non_coding_transcript_exon	Exon 4 of 4
	XGY2	ENST00000679518.1		n.106+12662A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	46,XY sex reversal 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.6
PROVEAN	Uncertain	-2.7	D
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
PromoterAI		-0.015	Neutral
Varity_R		0.59
gMVP		0.96
Mutation Taster		=13/87	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104894968;

hg19: chrY-2655442;