rs104894346

Variant names:

• chr12-49094511-A-G
• rs104894346
• NM_021044.4:c.2T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate 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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 99 codons. Genomic position: 49094218. Lost 0.248 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
DHH	NM_021044.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	ENST00000649637.2	NP_066382.1
LOC105369759	XR_007063295.1	n.392+323A>G		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHH	ENST00000649637.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 3		NM_021044.4	ENSP00000497483.1

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

Nov 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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
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;