16-66566526-C-G

Variant names:

• chr16-66566526-C-G
• rs750453605
• NM_052999.4:c.13C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052999.4(CMTM1):​c.13C>G​(p.His5Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H5Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CMTM1 NM_052999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28
• Publications: 0 publications found

Genes affected

CMTM1 (HGNC:19172): (CKLF like MARVEL transmembrane domain containing 1) 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. The protein encoded by this gene may play an important role in testicular development. Alternatively spliced transcript variants encoding different isoforms have been identified. Naturally occurring read-through transcription occurs between this locus and the neighboring locus CKLF (chemokine-like factor).[provided by RefSeq, Feb 2011]

CKLF-CMTM1 (HGNC:39977): (CKLF-CMTM1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring CKLF (chemokine-like factor) and CMTM1 (CKLF-like MARVEL transmembrane domain containing 1) genes on chromosome 16. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Feb 2011]

ENSG00000277978 (HGNC:):

CKLF (HGNC:13253): (chemokine like factor) The product of this gene is a cytokine. Cytokines are small proteins that have an essential role in the immune and inflammatory responses. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 16. The protein encoded by this gene is a potent chemoattractant for neutrophils, monocytes and lymphocytes. It also can stimulate the proliferation of skeletal muscle cells. This protein may play important roles in inflammation and in the regeneration of skeletal muscle. Alternatively spliced transcript variants encoding different isoforms have been identified. Naturally occurring read-through transcription occurs between this locus and the neighboring locus CMTM1 (CKLF-like MARVEL transmembrane domain containing 1).[provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029284626).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052999.4. 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
	CMTM1	NM_052999.4	MANE Select	c.13C>G	p.His5Asp	missense	Exon 1 of 4	NP_443725.3
	CMTM1	NM_181268.3		c.13C>G	p.His5Asp	missense	Exon 1 of 4	NP_851785.2	E9PAX0
	CMTM1	NM_181269.3		c.13C>G	p.His5Asp	missense	Exon 1 of 4	NP_851786.1	Q8IZ96-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMTM1	ENST00000379500.7	TSL:1 MANE Select	c.13C>G	p.His5Asp	missense	Exon 1 of 4	ENSP00000368814.2	Q8IZ96-17
	CMTM1	ENST00000533953.5	TSL:1	c.13C>G	p.His5Asp	missense	Exon 1 of 3	ENSP00000435786.1	E9PIL3
	CMTM1	ENST00000328020.10	TSL:1	c.13C>G	p.His5Asp	missense	Exon 1 of 4	ENSP00000330061.6	E9PAX0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455596 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723932

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109238

Other (OTH) AF: 0.00 AC: 0 AN: 60150

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.0010
DANN	Benign	0.42
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-2.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.026
Sift	Benign	1.0	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.097
MutPred		0.051		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.16
MPC		0.41
ClinPred		0.036	T
GERP RS		-3.8
PromoterAI		-0.010	Neutral
Varity_R		0.018
gMVP		0.033
Mutation Taster		=98/2	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: rs750453605; hg19: chr16-66600429;