NM_181553.4:c.82C>T

Variant names:

• chr16-66604887-C-T
• rs1293115978
• NM_181553.4:c.82C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181553.4(CMTM3):​c.82C>T​(p.Arg28Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,283,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CMTM3 NM_181553.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.403
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35241464).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181553.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMTM3	NM_181553.4	MANE Select	c.82C>T	p.Arg28Cys	missense	Exon 1 of 5	NP_853531.1	Q96MX0-1
	CMTM3	NM_001363918.2		c.82C>T	p.Arg28Cys	missense	Exon 2 of 6	NP_001350847.1	Q96MX0-1
	CMTM3	NM_001363923.2		c.82C>T	p.Arg28Cys	missense	Exon 2 of 6	NP_001350852.1	Q96MX0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMTM3	ENST00000567572.6	TSL:1 MANE Select	c.82C>T	p.Arg28Cys	missense	Exon 1 of 5	ENSP00000455851.1	Q96MX0-1
	CMTM3	ENST00000361909.8	TSL:1	c.82C>T	p.Arg28Cys	missense	Exon 2 of 6	ENSP00000354579.4	Q96MX0-1
	CMTM3	ENST00000565922.1	TSL:1	c.82C>T	p.Arg28Cys	missense	Exon 1 of 2	ENSP00000456426.1	Q96MX0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 62804 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000312 AC: 4 AN: 1283304 Hom.: 0 Cov.: 31 AF XY: 0.00000317 AC XY: 2 AN XY: 631722

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25592

American (AMR) AF: 0.00 AC: 0 AN: 20588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21716

East Asian (EAS) AF: 0.00 AC: 0 AN: 27524

South Asian (SAS) AF: 0.00 AC: 0 AN: 67208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4688

European-Non Finnish (NFE) AF: 0.00000388 AC: 4 AN: 1031160

Other (OTH) AF: 0.00 AC: 0 AN: 52718

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0522941), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.40
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.13
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.22
MutPred		0.37		Loss of solvent accessibility (P = 0.0079)
MVP		0.52
MPC		0.93
ClinPred		0.71	D
GERP RS		1.3
PromoterAI		-0.011	Neutral
Varity_R		0.16
gMVP		0.24
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs1293115978; hg19: chr16-66638790;