7-132885745-C-A

Position:

chr7-132885745-C-A

Variant summary

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

The NM_017812.4(CHCHD3):c.370G>T(p.Ala124Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000137 in 1,604,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CHCHD3
NM_017812.4 missense, splice_region

Scores

Splicing: ADA: 0.9985

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.69

Variant links:

Genes affected

CHCHD3 (HGNC:21906): (coiled-coil-helix-coiled-coil-helix domain containing 3) The protein encoded by this gene is an inner mitochondrial membrane scaffold protein. Absence of the encoded protein affects the structural integrity of mitochondrial cristae and leads to reductions in ATP production, cell growth, and oxygen consumption. This protein is part of the mitochondrial contact site and cristae organizing system (MICOS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

CHCHD3 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, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHCHD3	NM_017812.4 linkuse as main transcript	c.370G>T	p.Ala124Ser	missense_variant, splice_region_variant	5/8	ENST00000262570.10	NP_060282.1
CHCHD3	NM_001317177.2 linkuse as main transcript	c.385G>T	p.Ala129Ser	missense_variant, splice_region_variant	6/9		NP_001304106.1
CHCHD3	XM_047420549.1 linkuse as main transcript	c.274G>T	p.Ala92Ser	missense_variant, splice_region_variant	5/8		XP_047276505.1
CHCHD3	NR_133671.2 linkuse as main transcript	n.613G>T		splice_region_variant, non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CHCHD3	ENST00000262570.10 linkuse as main transcript	c.370G>T	p.Ala124Ser	missense_variant, splice_region_variant	5/8	1	NM_017812.4	ENSP00000262570	A1
CHCHD3	ENST00000423635.5 linkuse as main transcript	c.460G>T	p.Ala154Ser	missense_variant, splice_region_variant, NMD_transcript_variant	6/11	1		ENSP00000410425
CHCHD3	ENST00000448878.6 linkuse as main transcript	c.385G>T	p.Ala129Ser	missense_variant, splice_region_variant	6/9	5		ENSP00000389297	P3
CHCHD3	ENST00000496427.5 linkuse as main transcript	n.280G>T		splice_region_variant, non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

243464

Hom.:

AF XY:

0.0000228

AC XY:

AN XY:

131732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000565

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1452770

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722636

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000764

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000849

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

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

Mar 19, 2024

The c.370G>T (p.A124S) alteration is located in exon 5 (coding exon 5) of the CHCHD3 gene. This alteration results from a G to T substitution at nucleotide position 370, causing the alanine (A) at amino acid position 124 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Uncertain

-0.21

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.028

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.99

D;D

Vest4

0.54

MutPred

0.69

.;Loss of helix (P = 0.0167);

MVP

0.76

MPC

0.69

ClinPred

0.78

GERP RS

5.8

Varity_R

0.30

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.46

Position offset: -5

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