Genetic Variant DHH:p.Ala287Val (chr12-49090190-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_021044.4(DHH):c.860C>T(p.Ala287Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A287E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DHH
NM_021044.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.217

Publications

0 publications found

Variant links:

Genes affected

DHH (HGNC:2865): (desert hedgehog signaling molecule) This gene encodes a member of the hedgehog family. The hedgehog gene family encodes signaling molecules that play an important role in regulating morphogenesis. This protein is predicted to be made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the organism. Defects in this protein have been associated with partial gonadal dysgenesis (PGD) accompanied by minifascicular polyneuropathy. This protein may be involved in both male gonadal differentiation and perineurial development. [provided by RefSeq, May 2010]

DHH Gene-Disease associations (from GenCC):

46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
46,XY complete gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DHH links:

ENSG00000257346 (HGNC:58445):

ENSG00000257346 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2901881).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021044.4. 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
	DHH	NM_021044.4	MANE Select	c.860C>T	p.Ala287Val	missense	Exon 3 of 3	NP_066382.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHH	ENST00000649637.2	MANE Select	c.860C>T	p.Ala287Val	missense	Exon 3 of 3	ENSP00000497483.1
	ENSG00000257346	ENST00000553174.1	TSL:2	n.-18G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1397336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689152

African (AFR)

AF:

0.00

AC:

AN:

31588

American (AMR)

AF:

0.00

AC:

AN:

35718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25136

East Asian (EAS)

AF:

0.00

AC:

AN:

35748

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5446

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078816

Other (OTH)

AF:

0.00

AC:

AN:

57928

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.29

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

0.34

PhyloP100

0.22

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.43

Sift

Benign

0.23

Sift4G

Benign

0.24

Polyphen

0.017

Vest4

0.054

MutPred

0.36

Gain of catalytic residue at G284 (P = 8e-04)

MVP

0.99

MPC

0.99

ClinPred

0.22

GERP RS

3.7

Varity_R

0.11

gMVP

0.63

Mutation Taster

=90/10

polymorphism

(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