chr1-236849220-G-C

Variant names:

• chr1-236849220-G-C
• rs4659730
• NM_000254.3:c.1516-1124G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000254.3(MTR):​c.1516-1124G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 152,150 control chromosomes in the GnomAD database, including 1,942 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (1942 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.963
• Publications: 1 publications found

Genes affected

MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

MTR Gene-Disease associations (from GenCC):

• methylcobalamin deficiency type cblG

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.1516-1124G>C		intron_variant	Intron 15 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.1516-1124G>C		intron_variant	Intron 15 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.178-1124G>C		intron_variant	Intron 2 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23651 AN: 152032 Hom.: 1943 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.0814

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.140

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.156 AC: 23661 AN: 152150 Hom.: 1942 Cov.: 32 AF XY: 0.156 AC XY: 11588 AN XY: 74378

African (AFR) AF: 0.128 AC: 5312 AN: 41512

American (AMR) AF: 0.126 AC: 1929 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 570 AN: 3468

East Asian (EAS) AF: 0.0812 AC: 421 AN: 5184

South Asian (SAS) AF: 0.188 AC: 906 AN: 4816

European-Finnish (FIN) AF: 0.165 AC: 1743 AN: 10576

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.181 AC: 12281 AN: 67994

Other (OTH) AF: 0.143 AC: 302 AN: 2114

Alfa AF: 0.171 Hom.: 267

Bravo AF: 0.147

Asia WGS AF: 0.133 AC: 463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.69
DANN	Benign	0.71
PhyloP100		-0.96
Mutation Taster		=99/1	polymorphism (auto)

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: rs4659730; hg19: chr1-237012520;