12-49094511-A-G

Position:

• chr12-49094511-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_021044.4(DHH):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000713 in 1,401,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DHH NM_021044.4 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.12

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]

LOC105369759 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49094511-A-G is Pathogenic according to our data. Variant chr12-49094511-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5010.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-49094511-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHH	NM_021044.4	c.2T>C	p.Met1?	start_lost	1/3	ENST00000649637.2	NP_066382.1
LOC105369759	XR_007063295.1	n.392+323A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHH	ENST00000649637.2	c.2T>C	p.Met1?	start_lost	1/3		NM_021044.4	ENSP00000497483	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1401784 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000279

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 Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.53	D;D
Eigen	Benign	-0.079
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.3	D
MutationTaster	Benign	1.0	A
PROVEAN	Benign	-1.7	.;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0030	.;D
Polyphen		0.21	B;B
Vest4		0.96
MutPred		0.93		Gain of catalytic residue at N6 (P = 6e-04);Gain of catalytic residue at N6 (P = 6e-04);
MVP		0.99
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.60
gMVP		0.63

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

Other links and lift over

dbSNP: rs104894346; hg19: chr12-49488294;