16-66609502-A-G

Variant names:

• chr16-66609502-A-G
• NM_181553.4:c.371A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181553.4(CMTM3):​c.371A>G​(p.Tyr124Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CMTM3 NM_181553.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

Genes affected

CMTM3 (HGNC:19174): (CKLF like MARVEL transmembrane domain containing 3) This gene belongs to the chemokine-like factor gene superfamily, a novel family that is similar to the chemokine and the transmembrane 4 superfamilies of signaling molecules. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 16. Alternatively spliced transcript variants containing different 5' UTRs, but encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

CMTM4 (HGNC:19175): (CKLF like MARVEL transmembrane domain containing 4) This gene belongs to the chemokine-like factor gene superfamily, a novel family that is similar to the chemokine and the transmembrane 4 superfamilies of signaling molecules. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 16. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

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, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMTM3	NM_181553.4	c.371A>G	p.Tyr124Cys	missense_variant	Exon 3 of 5	ENST00000567572.6	NP_853531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMTM3	ENST00000567572.6	c.371A>G	p.Tyr124Cys	missense_variant	Exon 3 of 5	1	NM_181553.4	ENSP00000455851.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371A>G (p.Y124C) alteration is located in exon 4 (coding exon 3) of the CMTM3 gene. This alteration results from a A to G substitution at nucleotide position 371, causing the tyrosine (Y) at amino acid position 124 to be replaced by a cysteine (C). 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	0.50
BayesDel_addAF	Benign	0.0049	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;.;.;T;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;.;.;.;D;D;D;.;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.4	D;D;D;.;.;D;.;.;D
REVEL	Uncertain	0.31
Sift	Benign	0.047	D;D;D;.;.;D;.;.;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;D;.;.;.
Vest4		0.89
MutPred		0.55		Gain of methylation at K123 (P = 0.018);Gain of methylation at K123 (P = 0.018);Gain of methylation at K123 (P = 0.018);.;.;Gain of methylation at K123 (P = 0.018);.;.;.;
MVP		0.70
MPC		1.2
ClinPred		0.97	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.69

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: chr16-66643405;