chr12-49089640-C-T

Position:

• chr12-49089640-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021044.4(DHH):​c.*219G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0244 in 434,120 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (62 hom., cov: 32)
  • Exomes 𝑓: 0.026 (123 hom.)
• Consequence: DHH NM_021044.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.456

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=-0.77).
• BP6: Variant 12-49089640-C-T is Benign according to our data. Variant chr12-49089640-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 309094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0211 (3215/152266) while in subpopulation SAS AF= 0.0338 (163/4820). AF 95% confidence interval is 0.0307. There are 62 homozygotes in gnomad4. There are 1523 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 62 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHH	NM_021044.4	c.*219G>A		3_prime_UTR_variant	3/3	ENST00000649637.2	NP_066382.1
DHH	XM_017019380.2	c.*219G>A		3_prime_UTR_variant	3/3		XP_016874869.1
DHH	XM_017019381.2	c.*219G>A		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.*219G>A		3_prime_UTR_variant	3/3		NM_021044.4	ENSP00000497483	P1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3217 AN: 152148 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0278

GnomAD4 exome AF: 0.0262 AC: 7391 AN: 281854 Hom.: 123 Cov.: 4 AF XY: 0.0272 AC XY: 3905 AN XY: 143762

Gnomad4 AFR exome AF: 0.00534

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.0000432

Gnomad4 SAS exome AF: 0.0293

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.0315

Gnomad4 OTH exome AF: 0.0251

GnomAD4 genome AF: 0.0211 AC: 3215 AN: 152266 Hom.: 62 Cov.: 32 AF XY: 0.0205 AC XY: 1523 AN XY: 74456

Gnomad4 AFR AF: 0.00501

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0338

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0305 Hom.: 11

Bravo AF: 0.0192

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -

46,XY sex reversal 7 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs145466782; hg19: chr12-49483423;