Genetic Variant NM_003140.3:c.192G>C (chrY-2787412-C-G) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1PM1PP2PP3_Strong

The NM_003140.3(SRY):c.192G>C(p.Met64Ile) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 0)

Consequence

SRY
NM_003140.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.68

Publications

0 publications found

Variant links:

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]

SRY links:

XGY2 (HGNC:34022): (XG Y-linked 2 (pseudogene))

XGY2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS1

Transcript NM_003140.3 (SRY) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 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, 0.992

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.192G>C	p.Met64Ile	missense	Exon 1 of 1	NP_003131.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SRY	ENST00000383070.2	TSL:6 MANE Select	c.192G>C	p.Met64Ile	missense	Exon 1 of 1	ENSP00000372547.1
XGY2	ENST00000679825.1		n.524C>G		non_coding_transcript_exon	Exon 4 of 4
XGY2	ENST00000679518.1		n.106+12673C>G		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.89

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.1

PhyloP100

5.7

PROVEAN

Uncertain

-3.6

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

0.90

Vest4

0.75

MutPred

0.94

Loss of disorder (P = 0.0506)

MVP

1.0

MPC

1.1

ClinPred

0.97

GERP RS

0.64

PromoterAI

0.024

Neutral

(source)

Varity_R

0.66

gMVP

0.91

Mutation Taster

=6/94

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over