14-23378349-G-T

Position:

• chr14-23378349-G-T

Variant summary

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

The NM_001288746.2(CMTM5):​c.127G>T​(p.Ala43Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CMTM5 NM_001288746.2 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

Genes affected

CMTM5 (HGNC:19176): (CKLF like MARVEL transmembrane domain containing 5) This gene encodes a member of the chemokine-like factor superfamily. This family of genes encodes multi-pass membrane proteins that are similar to both the chemokine and the transmembrane 4 superfamilies of signaling molecules. The encoded protein may exhibit tumor suppressor activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

CMTM5 (HGNC:):

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
CMTM5	NM_001288746.2	c.127G>T	p.Ala43Ser	missense_variant, splice_region_variant	2/6	ENST00000339180.9	NP_001275675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CMTM5	ENST00000339180.9	c.127G>T	p.Ala43Ser	missense_variant, splice_region_variant	2/6	1	NM_001288746.2	ENSP00000344819.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 25, 2024

The c.127G>T (p.A43S) alteration is located in exon 2 (coding exon 2) of the CMTM5 gene. This alteration results from a G to T substitution at nucleotide position 127, causing the alanine (A) at amino acid position 43 to be replaced by a serine (S). 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	0.34
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	.;.;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.80	.;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	.;N;N;N
REVEL	Benign	0.053
Sift	Uncertain	0.028	.;D;T;T
Sift4G	Uncertain	0.044	.;D;D;T
Polyphen		0.45	B;B;D;.
Vest4		0.23, 0.18, 0.23
MutPred		0.48		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.54
MPC		0.37
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.11
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.090		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: chr14-23847558;