Variant 18-47134663-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032124.5(HDHD2):c.143C>A(p.Thr48Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,614,036 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: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

HDHD2
NM_032124.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.78

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDHD2	NM_032124.5 linkuse as main transcript	c.143C>A	p.Thr48Lys	missense_variant	3/7	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.143C>A	p.Thr48Lys	missense_variant	3/7	1	NM_032124.5	ENSP00000300605.4	Q9H0R4-1
ENSG00000267228	ENST00000588705.1 linkuse as main transcript	n.*301C>A		non_coding_transcript_exon_variant	6/6	2		ENSP00000465194.1
ENSG00000267228	ENST00000588705.1 linkuse as main transcript	n.*301C>A		3_prime_UTR_variant	6/6	2		ENSP00000465194.1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251328

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000370

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000407

AC:

595

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000373

AC XY:

271

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000504

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000250

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000362

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

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

May 15, 2024

The c.143C>A (p.T48K) alteration is located in exon 3 (coding exon 2) of the HDHD2 gene. This alteration results from a C to A substitution at nucleotide position 143, causing the threonine (T) at amino acid position 48 to be replaced by a lysine (K). 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

0.94

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

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

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.089

MetaRNN

Pathogenic

0.79

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

MetaSVM

Uncertain

-0.22

MutationAssessor

Pathogenic

3.6

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

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.6

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

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0070

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

Polyphen

1.0

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

Vest4

0.90

MVP

0.52

MPC

0.89

ClinPred

0.95

GERP RS

5.0

Varity_R

0.98

gMVP

0.88

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

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