12-49090218-C-G

Position:

• chr12-49090218-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021044.4(DHH):​c.832G>C​(p.Gly278Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHH NM_021044.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.221

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21442467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHH	NM_021044.4	c.832G>C	p.Gly278Arg	missense_variant	3/3	ENST00000649637.2
DHH	XM_017019380.2	c.691G>C	p.Gly231Arg	missense_variant	3/3
DHH	XM_017019381.2	c.490G>C	p.Gly164Arg	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHH	ENST00000649637.2	c.832G>C	p.Gly278Arg	missense_variant	3/3		NM_021044.4	P1
	ENST00000553174.1	n.11C>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.61	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	0.030	D
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.90	D
Polyphen		0.0010	B;B
Vest4		0.069
MutPred		0.39		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.98
MPC		1.7
ClinPred		0.63	D
GERP RS		4.8
Varity_R		0.11
gMVP		0.65

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: rs1939272322; hg19: chr12-49484001;