NM_181521.3:c.330C>A

Variant names:

• chr16-66636438-G-T
• NM_181521.3:c.330C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_181521.3(CMTM4):​c.330C>A​(p.His110Gln) variant causes a missense change involving the alteration of a non-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: 32)
• Consequence: CMTM4 NM_181521.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

Genes affected

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMTM4	NM_181521.3	c.330C>A	p.His110Gln	missense_variant	Exon 2 of 4	ENST00000394106.7	NP_852662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMTM4	ENST00000394106.7	c.330C>A	p.His110Gln	missense_variant	Exon 2 of 4	1	NM_181521.3	ENSP00000377666.2
CMTM4	ENST00000330687.8	c.330C>A	p.His110Gln	missense_variant	Exon 2 of 5	1		ENSP00000333833.4
CMTM4	ENST00000563952.1	c.243C>A	p.His81Gln	missense_variant	Exon 2 of 4	1		ENSP00000456380.1
CMTM4	ENST00000561680.5	c.48C>A	p.His16Gln	missense_variant	Exon 1 of 5	2		ENSP00000464316.1

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

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.330C>A (p.H110Q) alteration is located in exon 2 (coding exon 2) of the CMTM4 gene. This alteration results from a C to A substitution at nucleotide position 330, causing the histidine (H) at amino acid position 110 to be replaced by a glutamine (Q). 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	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.2	D;.;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.085	T;.;T;T
Sift4G	Benign	0.096	T;D;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.82
MutPred		0.80		Gain of catalytic residue at Q115 (P = 0.1501);.;Gain of catalytic residue at Q115 (P = 0.1501);.;
MVP		0.29
MPC		1.4
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.43
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: chr16-66670341;