Genetic Variant CHCHD4:p.Arg92Gln (chr3-14113041-C-T) – 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_001098502.2(CHCHD4):c.275G>A(p.Arg92Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000998 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

CHCHD4
NM_001098502.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79

Variant links:

Genes affected

CHCHD4 (HGNC:26467): (coiled-coil-helix-coiled-coil-helix domain containing 4) CHCHD4, a component of human mitochondria, belongs to a protein family whose members share 6 highly conserved cysteine residues constituting a -CXC-CX(9)C-CX(9)C- motif in the C terminus (Hofmann et al., 2005 [PubMed 16185709]).[supplied by OMIM, Mar 2008]

CHCHD4 links:

Genome browser will be placed here

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=0.22031748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD4	NM_001098502.2 link	c.275G>A	p.Arg92Gln	missense_variant	Exon 3 of 3	ENST00000396914.4	NP_001091972.1	Q8N4Q1-1A0A024R2I5
CHCHD4	NM_144636.3 link	c.314G>A	p.Arg105Gln	missense_variant	Exon 4 of 4		NP_653237.1	Q8N4Q1-2A0A024R2F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHCHD4	ENST00000396914.4 link	c.275G>A	p.Arg92Gln	missense_variant	Exon 3 of 3	1	NM_001098502.2	ENSP00000380122.3	Q8N4Q1-1
CHCHD4	ENST00000295767.9 link	c.314G>A	p.Arg105Gln	missense_variant	Exon 4 of 4	2		ENSP00000295767.5	Q8N4Q1-2
CHCHD4	ENST00000420103.1 link	n.*103G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000723

AC:

AN:

249012

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000923

AC:

135

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727244

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:

0.0000374

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000171

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000152

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.314G>A (p.R105Q) alteration is located in exon 4 (coding exon 3) of the CHCHD4 gene. This alteration results from a G to A substitution at nucleotide position 314, causing the arginine (R) at amino acid position 105 to be replaced by a glutamine (Q). 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

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.14

.;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.23

Sift

Benign

0.49

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.27

B;D

Vest4

0.32

MVP

0.87

MPC

0.31

ClinPred

0.19

GERP RS

5.6

Varity_R

0.50

gMVP

0.53

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