Variant chr18-47136402-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_032124.5(HDHD2):c.38A>T(p.Asp13Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,794 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HDHD2
NM_032124.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.88

Variant links:

Genes affected

HDHD2 (HGNC:25364): (haloacid dehalogenase like hydrolase domain containing 2) Enables enzyme binding activity. Predicted to be involved in dephosphorylation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

HDHD2 links:

ENSG00000267228 (HGNC:):

ENSG00000267228 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity HDHD2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDHD2	NM_032124.5 linkuse as main transcript	c.38A>T	p.Asp13Val	missense_variant	2/7	ENST00000300605.11	NP_115500.1	Q9H0R4-1V9HW73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HDHD2	ENST00000300605.11 linkuse as main transcript	c.38A>T	p.Asp13Val	missense_variant	2/7	1	NM_032124.5	ENSP00000300605.4	Q9H0R4-1
ENSG00000267228	ENST00000588705.1 linkuse as main transcript	n.*196A>T		non_coding_transcript_exon_variant	5/6	2		ENSP00000465194.1
ENSG00000267228	ENST00000588705.1 linkuse as main transcript	n.*196A>T		3_prime_UTR_variant	5/6	2		ENSP00000465194.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249934

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460794

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726802

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.38A>T (p.D13V) alteration is located in exon 2 (coding exon 1) of the HDHD2 gene. This alteration results from a A to T substitution at nucleotide position 38, causing the aspartic acid (D) at amino acid position 13 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.;T;.;.;T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-8.0

D;.;.;.;.;.;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;D;.;D;.;D

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.99

MutPred

0.91

Gain of MoRF binding (P = 0.0304);Gain of MoRF binding (P = 0.0304);Gain of MoRF binding (P = 0.0304);Gain of MoRF binding (P = 0.0304);Gain of MoRF binding (P = 0.0304);Gain of MoRF binding (P = 0.0304);Gain of MoRF binding (P = 0.0304);

MVP

1.0

MPC

0.97

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.97

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over