chr6-37476160-T-G

Position:

• chr6-37476160-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015050.3(CMTR1):​c.2071T>G​(p.Ser691Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CMTR1 NM_015050.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

CMTR1 (HGNC:21077): (cap methyltransferase 1) Enables mRNA (nucleoside-2'-O-)-methyltransferase activity. Involved in 7-methylguanosine mRNA capping and cap1 mRNA methylation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1307626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CMTR1	NM_015050.3	c.2071T>G	p.Ser691Ala	missense_variant	20/24	ENST00000373451.9	NP_055865.1
CMTR1	XM_047418462.1	c.2071T>G	p.Ser691Ala	missense_variant	21/25		XP_047274418.1
CMTR1	XM_047418463.1	c.2071T>G	p.Ser691Ala	missense_variant	22/26		XP_047274419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CMTR1	ENST00000373451.9	c.2071T>G	p.Ser691Ala	missense_variant	20/24	1	NM_015050.3	ENSP00000362550	P1
CMTR1	ENST00000457419.1	c.130T>G	p.Ser44Ala	missense_variant	2/6	3		ENSP00000393893
CMTR1	ENST00000475364.1	c.*448T>G		3_prime_UTR_variant, NMD_transcript_variant	4/7	5		ENSP00000432114

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 22, 2023

The c.2071T>G (p.S691A) alteration is located in exon 20 (coding exon 19) of the CMTR1 gene. This alteration results from a T to G substitution at nucleotide position 2071, causing the serine (S) at amino acid position 691 to be replaced by an alanine (A). 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	0.066
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.80	T
Sift4G	Benign	0.83	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.24		Loss of disorder (P = 0.0551);
MVP		0.42
MPC		0.67
ClinPred		0.68	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1264940723; hg19: chr6-37443936;