16-66604845-C-A

Variant names:

• chr16-66604845-C-A
• rs760528469
• NM_181553.4:c.40C>A

Variant summary

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

The NM_181553.4(CMTM3):​c.40C>A​(p.Pro14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 1,358,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CMTM3 NM_181553.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.211

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 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=0.047492802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMTM3	NM_181553.4	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 5	ENST00000567572.6	NP_853531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMTM3	ENST00000567572.6	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 5	1	NM_181553.4	ENSP00000455851.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152030 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000829 AC: 10 AN: 1206184 Hom.: 0 Cov.: 31 AF XY: 0.00000680 AC XY: 4 AN XY: 588468

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000252

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: 0.00000302

Gnomad4 OTH exome AF: 0.0000814

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74386

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000257

ExAC AF: 0.0000687 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40C>A (p.P14T) alteration is located in exon 2 (coding exon 1) of the CMTM3 gene. This alteration results from a C to A substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by a threonine (T). 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	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.87
DEOGEN2	Benign	0.0078	T;T;.;T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.57	T;.;T;.;.;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.047	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;.;N;N;N;.;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.13	N;N;N;N;N;N;N;D
REVEL	Benign	0.039
Sift	Benign	0.24	T;T;T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T;T;T
Polyphen		0.030	.;B;.;B;B;B;.;.
Vest4		0.084, 0.083, 0.088, 0.064
MutPred		0.090		Gain of phosphorylation at P14 (P = 0.0078);Gain of phosphorylation at P14 (P = 0.0078);Gain of phosphorylation at P14 (P = 0.0078);Gain of phosphorylation at P14 (P = 0.0078);Gain of phosphorylation at P14 (P = 0.0078);Gain of phosphorylation at P14 (P = 0.0078);Gain of phosphorylation at P14 (P = 0.0078);Gain of phosphorylation at P14 (P = 0.0078);
MVP		0.14
MPC		0.36
ClinPred		0.098	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.031
gMVP		0.40

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: rs760528469; hg19: chr16-66638748;