3-14112970-T-C

Variant names:

• chr3-14112970-T-C
• rs1313656695
• NM_001098502.2:c.346A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001098502.2(CHCHD4):​c.346A>G​(p.Arg116Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 6.8e-7 (0 hom.)
• Consequence: CHCHD4 NM_001098502.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0598996).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD4	NM_001098502.2	c.346A>G	p.Arg116Gly	missense_variant	Exon 3 of 3	ENST00000396914.4	NP_001091972.1
CHCHD4	NM_144636.3	c.385A>G	p.Arg129Gly	missense_variant	Exon 4 of 4		NP_653237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD4	ENST00000396914.4	c.346A>G	p.Arg116Gly	missense_variant	Exon 3 of 3	1	NM_001098502.2	ENSP00000380122.3
CHCHD4	ENST00000295767.9	c.385A>G	p.Arg129Gly	missense_variant	Exon 4 of 4	2		ENSP00000295767.5
CHCHD4	ENST00000420103.1	n.*174A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247412 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 133994

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461202 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726862

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.385A>G (p.R129G) alteration is located in exon 4 (coding exon 3) of the CHCHD4 gene. This alteration results from a A to G substitution at nucleotide position 385, causing the arginine (R) at amino acid position 129 to be replaced by a glycine (G). 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	0.060
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.021	.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.018
Sift	Benign	0.36	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.46	.;P
Vest4		0.13
MutPred		0.17		.;Loss of helix (P = 0.0093);
MVP		0.29
MPC		0.32
ClinPred		0.082	T
GERP RS		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.15

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

Other links and lift over

dbSNP: rs1313656695; hg19: chr3-14154470;