Genetic Variant HDHD5:p.Arg416Cys (chr22-17138047-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_033070.3(HDHD5):c.1246C>T(p.Arg416Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00521 in 1,613,076 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 37 hom. )

Consequence

HDHD5
NM_033070.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.419

Variant links:

Genes affected

HDHD5 (HGNC:1843): (haloacid dehalogenase like hydrolase domain containing 5) Predicted to be involved in glycerophospholipid biosynthetic process. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

HDHD5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048992634).

BP6

Variant 22-17138047-G-A is Benign according to our data. Variant chr22-17138047-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 782633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDHD5	NM_033070.3 link	c.1246C>T	p.Arg416Cys	missense_variant	Exon 8 of 8	ENST00000336737.8	NP_149061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDHD5	ENST00000336737.8 link	c.1246C>T	p.Arg416Cys	missense_variant	Exon 8 of 8	1	NM_033070.3	ENSP00000337358.4		Q9BXW7-1

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

626

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00664

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00416

AC:

1043

AN:

250472

Hom.:

AF XY:

0.00444

AC XY:

601

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00324

Gnomad ASJ exome

AF:

0.000799

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00745

Gnomad FIN exome

AF:

0.00204

Gnomad NFE exome

AF:

0.00542

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.00533

AC:

7781

AN:

1460882

Hom.:

Cov.:

AF XY:

0.00551

AC XY:

4003

AN XY:

726562

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.00347

Gnomad4 ASJ exome

AF:

0.000881

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00776

Gnomad4 FIN exome

AF:

0.00253

Gnomad4 NFE exome

AF:

0.00577

Gnomad4 OTH exome

AF:

0.00510

GnomAD4 genome

AF:

0.00412

AC:

627

AN:

152194

Hom.:

Cov.:

AF XY:

0.00405

AC XY:

301

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00104

Gnomad4 AMR

AF:

0.00870

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00665

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00559

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00498

Hom.:

Bravo

AF:

0.00417

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00409

AC:

496

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00646

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

.;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.0086

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Benign

0.044

Sift

Benign

0.067

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.10

B;B;B

Vest4

0.14

MVP

0.15

MPC

0.25

ClinPred

0.025

GERP RS

2.2

Varity_R

0.18

gMVP

0.32

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