3-32441897-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138410.4(CMTM7):c.217G>A(p.Ala73Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,880 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: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CMTM7 NM_138410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

Genes affected

CMTM7 (HGNC:19178): (CKLF like MARVEL transmembrane domain containing 7) This gene belongs to the chemokine-like factor gene superfamily, a novel family that is similar to the chemokine and transmembrane 4 superfamilies. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 3. This gene acts as a tumor suppressor that regulates G1/S transition in the cell cycle, and epidermal growth factor receptor/protein kinase B signaling during tumor pathogenesis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39693066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CMTM7	NM_138410.4	c.217G>A	p.Ala73Thr	missense_variant	2/5	ENST00000334983.10
CMTM7	NM_181472.3	c.217G>A	p.Ala73Thr	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CMTM7	ENST00000334983.10	c.217G>A	p.Ala73Thr	missense_variant	2/5	1	NM_138410.4	P1
CMTM7	ENST00000349718.8	c.217G>A	p.Ala73Thr	missense_variant	2/4	1
CMTM7	ENST00000465248.1	c.85G>A	p.Ala29Thr	missense_variant	2/3	2
CMTM7	ENST00000454304.6	c.217G>A	p.Ala73Thr	missense_variant, NMD_transcript_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251476 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000413 Hom.: 0

Bravo AF: 0.00000756

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

Aug 20, 2023

The c.217G>A (p.A73T) alteration is located in exon 2 (coding exon 2) of the CMTM7 gene. This alteration results from a G to A substitution at nucleotide position 217, causing the alanine (A) at amino acid position 73 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	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.055	T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N;D;D
REVEL	Benign	0.093
Sift	Benign	0.067	T;T;D
Sift4G	Benign	0.13	T;T;D
Polyphen		0.85	P;.;.
Vest4		0.29
MutPred		0.72		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;
MVP		0.51
MPC		0.49
ClinPred		0.69	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.66

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: rs1017441804; hg19: chr3-32483389; COSMIC: COSV58550925;