Genetic Variant HDHD5:p.Met247Ile (chr22-17141064-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_033070.3(HDHD5):c.741G>T(p.Met247Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000489 in 1,430,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

HDHD5
NM_033070.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26461828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDHD5	NM_033070.3 link	c.741G>T	p.Met247Ile	missense_variant	Exon 6 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.741G>T	p.Met247Ile	missense_variant	Exon 6 of 8	1	NM_033070.3	ENSP00000337358.4		Q9BXW7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000904

AC:

AN:

221120

Hom.:

AF XY:

0.00000828

AC XY:

AN XY:

120820

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:

0.0000197

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000489

AC:

AN:

1430754

Hom.:

Cov.:

AF XY:

0.00000422

AC XY:

AN XY:

711284

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00000455

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.00000756

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

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.741G>T (p.M247I) alteration is located in exon 6 (coding exon 6) of the CECR5 gene. This alteration results from a G to T substitution at nucleotide position 741, causing the methionine (M) at amino acid position 247 to be replaced by an isoleucine (I). 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

.;T;.

Eigen

Benign

0.082

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.071

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.67

T;T;T

Polyphen

0.029

B;B;D

Vest4

0.59

MutPred

0.39

.;Gain of methylation at K246 (P = 0.0252);.;

MVP

0.27

MPC

0.21

ClinPred

0.28

GERP RS

4.3

Varity_R

0.22

gMVP

0.82

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