12-49090137-C-T

Variant names:

• chr12-49090137-C-T
• rs1939270334
• NM_021044.4:c.913G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021044.4(DHH):​c.913G>A​(p.Gly305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000132 in 1,510,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: DHH NM_021044.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.474
• Publications: 0 publications found

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]

DHH Gene-Disease associations (from GenCC):

• 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000257346 (HGNC:58445):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHH	NM_021044.4	c.913G>A	p.Gly305Arg	missense_variant	Exon 3 of 3	ENST00000649637.2	NP_066382.1
DHH	XM_017019380.2	c.772G>A	p.Gly258Arg	missense_variant	Exon 3 of 3		XP_016874869.1
DHH	XM_017019381.2	c.571G>A	p.Gly191Arg	missense_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.913G>A	p.Gly305Arg	missense_variant	Exon 3 of 3		NM_021044.4	ENSP00000497483.1
ENSG00000257346	ENST00000553174.1	n.-71C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1358006 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 667320

African (AFR) AF: 0.0000354 AC: 1 AN: 28256

American (AMR) AF: 0.00 AC: 0 AN: 29982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22786

East Asian (EAS) AF: 0.00 AC: 0 AN: 33602

South Asian (SAS) AF: 0.00 AC: 0 AN: 73448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5372

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061970

Other (OTH) AF: 0.00 AC: 0 AN: 56110

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74372

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Disorder of sexual differentiation Uncertain:1

Aug 15, 2021

Human Developmental Genetics, Institut Pasteur

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Benign	0.15
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.29	.;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.3	L;L
PhyloP100		0.47
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.9	.;N
REVEL	Uncertain	0.53
Sift	Benign	0.24	.;T
Sift4G	Benign	0.24	.;T
Polyphen		0.99	D;D
Vest4		0.17
MutPred		0.54		Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);
MVP		0.98
MPC		1.3
ClinPred		0.84	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.85
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs1939270334; hg19: chr12-49483920;