12-49090115-C-T

Position:

• chr12-49090115-C-T

Variant summary

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

The NM_021044.4(DHH):​c.935G>A​(p.Arg312His) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHH NM_021044.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0640

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]

ACMG classification

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	UniProt
DHH	NM_021044.4	c.935G>A	p.Arg312His	missense_variant	3/3	ENST00000649637.2	NP_066382.1
DHH	XM_017019380.2	c.794G>A	p.Arg265His	missense_variant	3/3		XP_016874869.1
DHH	XM_017019381.2	c.593G>A	p.Arg198His	missense_variant	3/3		XP_016874870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHH	ENST00000649637.2	c.935G>A	p.Arg312His	missense_variant	3/3		NM_021044.4	ENSP00000497483	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.935G>A (p.R312H) alteration is located in exon 3 (coding exon 3) of the DHH gene. This alteration results from a G to A substitution at nucleotide position 935, causing the arginine (R) at amino acid position 312 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.80	.;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	.;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.016	.;D
Sift4G	Uncertain	0.019	.;D
Polyphen		0.98	D;D
Vest4		0.20
MutPred		0.58		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.99
MPC		2.3
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.12
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49483898;