Genetic Variant HDHD5:p.Val403Leu (chr22-17138086-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033070.3(HDHD5):c.1207G>T(p.Val403Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

HDHD5
NM_033070.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.988

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.099217355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDHD5	NM_033070.3 link	c.1207G>T	p.Val403Leu	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.1207G>T	p.Val403Leu	missense_variant	Exon 8 of 8	1	NM_033070.3	ENSP00000337358.4		Q9BXW7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251312

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1207G>T (p.V403L) alteration is located in exon 8 (coding exon 8) of the CECR5 gene. This alteration results from a G to T substitution at nucleotide position 1207, causing the valine (V) at amino acid position 403 to be replaced by a leucine (L). 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

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.3

DANN

Benign

0.93

DEOGEN2

Benign

0.019

.;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.082

Sift

Benign

0.090

T;T;D

Sift4G

Benign

0.075

T;T;D

Polyphen

0.82

P;P;P

Vest4

0.12

MutPred

0.37

.;Gain of helix (P = 0.132);.;

MVP

0.072

MPC

0.21

ClinPred

0.47

GERP RS

-4.1

Varity_R

0.059

gMVP

0.35

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