chr3-28241798-C-T

Position:

• chr3-28241798-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_182523.2(CMC1):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000919 in 1,087,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: CMC1 NM_182523.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

Genes affected

CMC1 (HGNC:28783): (C-X9-C motif containing 1) Predicted to enable metal ion binding activity. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

CMC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity COXM1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42217436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CMC1	NM_182523.2	c.5C>T	p.Ala2Val	missense_variant	1/4	ENST00000466830.6	NP_872329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CMC1	ENST00000466830.6	c.5C>T	p.Ala2Val	missense_variant	1/4	1	NM_182523.2	ENSP00000418348.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000919 AC: 10 AN: 1087878 Hom.: 0 Cov.: 31 AF XY: 0.00000973 AC XY: 5 AN XY: 513818

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: 0.0000510

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000978

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 01, 2024

The c.5C>T (p.A2V) alteration is located in exon 1 (coding exon 1) of the CMC1 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a valine (V). 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	0.44
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.46
MutPred		0.32		Loss of catalytic residue at A2 (P = 0.2235);Loss of catalytic residue at A2 (P = 0.2235);
MVP		0.19
MPC		0.018
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.14
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1698530962; hg19: chr3-28283289;