rs104894346

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 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

DHH-AS1 (HGNC:58445):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 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 VariationId is 5010.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021044.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHH	NM_021044.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	NP_066382.1	O43323

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHH	ENST00000649637.2	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	ENSP00000497483.1	O43323

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

African (AFR) AF: 0.00 AC: 0 AN: 31708

American (AMR) AF: 0.00 AC: 0 AN: 35906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35868

South Asian (SAS) AF: 0.00 AC: 0 AN: 80290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081046

Other (OTH) AF: 0.00 AC: 0 AN: 58122

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Pathogenic	1.3	D
PhyloP100		4.1
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.21	B
Vest4		0.96
MutPred		0.93		Gain of catalytic residue at N6 (P = 6e-04)
MVP		0.99
ClinPred		0.98	D
GERP RS		5.0
PromoterAI		0.025	Neutral
Varity_R		0.60
gMVP		0.63
Mutation Taster		=12/188	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

Other links and lift over

dbSNP: rs104894346; hg19: chr12-49488294;