12-49089772-C-A

Position:

• chr12-49089772-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021044.4(DHH):​c.*87G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,411,322 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (228 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (142 hom.)
• Consequence: DHH NM_021044.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.32

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-49089772-C-A is Benign according to our data. Variant chr12-49089772-C-A is described in ClinVar as [Benign]. Clinvar id is 309097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHH	NM_021044.4	c.*87G>T		3_prime_UTR_variant	3/3	ENST00000649637.2	NP_066382.1
DHH	XM_017019380.2	c.*87G>T		3_prime_UTR_variant	3/3		XP_016874869.1
DHH	XM_017019381.2	c.*87G>T		3_prime_UTR_variant	3/3		XP_016874870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHH	ENST00000649637.2	c.*87G>T		3_prime_UTR_variant	3/3		NM_021044.4	ENSP00000497483	P1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4537 AN: 151966 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0191

GnomAD4 exome AF: 0.00262 AC: 3299 AN: 1259238 Hom.: 142 Cov.: 25 AF XY: 0.00236 AC XY: 1439 AN XY: 609914

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00613

Gnomad4 ASJ exome AF: 0.000163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000438

Gnomad4 FIN exome AF: 0.0000271

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00587

GnomAD4 genome AF: 0.0300 AC: 4555 AN: 152084 Hom.: 228 Cov.: 32 AF XY: 0.0287 AC XY: 2136 AN XY: 74374

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0219 Hom.: 16

Bravo AF: 0.0347

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2018	- -

46,XY sex reversal 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.6
DANN	Benign	0.63

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: rs75012285; hg19: chr12-49483555;