12-49090038-CG-C

Variant names:

• chr12-49090038-CG-C
• rs1565572949
• NM_021044.4:c.1011delC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_021044.4(DHH):​c.1011delC​(p.Asn337LysfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHH NM_021044.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.433

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]

ENSG00000257346 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.151 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49090038-CG-C is Pathogenic according to our data. Variant chr12-49090038-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 561188.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHH	NM_021044.4	c.1011delC	p.Asn337LysfsTer24	frameshift_variant	Exon 3 of 3	ENST00000649637.2	NP_066382.1
DHH	XM_017019380.2	c.870delC	p.Asn290LysfsTer24	frameshift_variant	Exon 3 of 3		XP_016874869.1
DHH	XM_017019381.2	c.669delC	p.Asn223LysfsTer24	frameshift_variant	Exon 3 of 3		XP_016874870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHH	ENST00000649637.2	c.1011delC	p.Asn337LysfsTer24	frameshift_variant	Exon 3 of 3		NM_021044.4	ENSP00000497483.1
ENSG00000257346	ENST00000553174.1	n.-169delG		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 7 Pathogenic:1

-

Human Genetics Laboratory, Faculty of Medicine of Tunis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

Direct sequencing of exons 1, 2 and 3 of DHH gene in a patient with 46,XY karyotype and complete gonadal dysgenesis, revealed a one nucleotide deletion in exon 3 at position 1011 (c.1011delC) resulting in a substitution of an asparagine (N) residue by a lysine (K) residue at amino acid position 337 in the C-terminal part of the protein (DHhC) and a frameshift with the apparition of a premature stop codon, 24 codons after the deletion was located p.(Asn337Lysfs*24). Thus, this variation generates a truncated protein lacking the last 60 amino acids of the C-terminal region containing the determinants required for auto-processing of the precursor as well as all the essential residues fundamental for addition of a cholesterol moiety to the signaling peptide DHh-N. This mutation was found associated as a compound heterozygous mutation in DHh-N in a patient with CGD. The second mutation is a nonsense mutation which lies in the auto-catalytically processed and secreted DHh-N and gives rise to a premature stop codon leading to a truncated protein missing a part of DHh-N as well as the entire DHh-C required for auto-processing and addition of cholesterol moiety to the signaling peptide DHh-N. The novel variation p.(Asn337Lysfs*24) is not listed in gnomAD browser database (http://gnomad.broadinstitute.org) or the Human Gene Mutations Database (HGMD) (http://www.hgmd.org/) or 1000 genomes project which likely reflects a novel mutation. The pathogenicity prediction algorithm, Mutation Taster, considered the frameshift p.(Asn337Lysfs*24) mutation as disease causing. In addition, our in vitro functional assays show that this variant completely abolished auto-proteolysis of the mutant protein. In summary, the Asn337Lysfs*24 variant meets our criteria to be classified as autosomal recessive pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=7/193	disease causing (ClinVar)

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: rs1565572949; hg19: chr12-49483821;