NM_021044.4:c.1027T>C

Variant names:

• chr12-49090023-A-G
• rs867798393
• NM_021044.4:c.1027T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_021044.4(DHH):​c.1027T>C​(p.Cys343Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DHH NM_021044.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.67
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 12-49090023-A-G is Pathogenic according to our data. Variant chr12-49090023-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 265768.Status of the report is criteria_provided_single_submitter, 1 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.1027T>C	p.Cys343Arg	missense	Exon 3 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.1027T>C	p.Cys343Arg	missense	Exon 3 of 3	ENSP00000497483.1	O43323
	ENSG00000257346	ENST00000553174.1	TSL:2	n.-185A>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404632 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693802

African (AFR) AF: 0.00 AC: 0 AN: 32006

American (AMR) AF: 0.00 AC: 0 AN: 36424

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 36490

South Asian (SAS) AF: 0.00 AC: 0 AN: 79852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083952

Other (OTH) AF: 0.00 AC: 0 AN: 58344

GnomAD4 genome Cov.: 32

Alfa AF: 0.000131 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	46,XY sex reversal 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
PhyloP100		5.7
Varity_R		0.88
gMVP		0.99
Mutation Taster		=42/58	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs867798393; hg19: chr12-49483806;