7-132785644-C-T

Position:

• chr7-132785644-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017812.4(CHCHD3):​c.677G>A​(p.Gly226Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHCHD3 NM_017812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD3	NM_017812.4	c.677G>A	p.Gly226Glu	missense_variant	8/8	ENST00000262570.10	NP_060282.1
CHCHD3	NM_001317177.2	c.692G>A	p.Gly231Glu	missense_variant	9/9		NP_001304106.1
CHCHD3	XM_047420549.1	c.581G>A	p.Gly194Glu	missense_variant	8/8		XP_047276505.1
CHCHD3	NR_133671.2	n.1211G>A		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD3	ENST00000262570.10	c.677G>A	p.Gly226Glu	missense_variant	8/8	1	NM_017812.4	ENSP00000262570	A1
CHCHD3	ENST00000423635.5	c.*332G>A		3_prime_UTR_variant, NMD_transcript_variant	11/11	1		ENSP00000410425
CHCHD3	ENST00000448878.6	c.692G>A	p.Gly231Glu	missense_variant	9/9	5		ENSP00000389297	P3
CHCHD3	ENST00000496427.5	n.587G>A		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

The c.677G>A (p.G226E) alteration is located in exon 8 (coding exon 8) of the CHCHD3 gene. This alteration results from a G to A substitution at nucleotide position 677, causing the glycine (G) at amino acid position 226 to be replaced by a glutamic acid (E). 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	Pathogenic	0.67
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.24		.;Gain of solvent accessibility (P = 0.024);
MVP		0.75
MPC		0.76
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.28
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-132470405;