Variant 12-49090137-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021044.4(DHH):c.913G>A(p.Gly305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000132 in 1,510,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

DHH
NM_021044.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.474

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DHH	NM_021044.4 linkuse as main transcript	c.913G>A	p.Gly305Arg	missense_variant	3/3	ENST00000649637.2	NP_066382.1
DHH	XM_017019380.2 linkuse as main transcript	c.772G>A	p.Gly258Arg	missense_variant	3/3		XP_016874869.1
DHH	XM_017019381.2 linkuse as main transcript	c.571G>A	p.Gly191Arg	missense_variant	3/3		XP_016874870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHH	ENST00000649637.2 linkuse as main transcript	c.913G>A	p.Gly305Arg	missense_variant	3/3		NM_021044.4	ENSP00000497483	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

AF:

7.36e-7

AC:

AN:

1358006

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

667320

show subpopulations

Gnomad4 AFR exome

AF:

0.0000354

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Disorder of sexual differentiation

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Human Developmental Genetics, Institut Pasteur

Aug 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D

Eigen

Benign

0.15

Eigen_PC

Benign

0.086

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.29

.;T

M_CAP

Pathogenic

0.93

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.9

.;N

REVEL

Uncertain

0.53

Sift

Benign

0.24

.;T

Sift4G

Benign

0.24

.;T

Polyphen

0.99

D;D

Vest4

0.17

MutPred

0.54

Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);

MVP

0.98

MPC

1.3

ClinPred

0.84

GERP RS

4.8

Varity_R

0.13

gMVP

0.85

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over