rs575057926

Variant names:

• chr1-236795360-C-T
• rs575057926
• NM_000254.3:c.-344C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000254.3(MTR):​c.-344C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,358,146 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: MTR NM_000254.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0510
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.027).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000545 (83/152342) while in subpopulation SAS AF = 0.00228 (11/4834). AF 95% confidence interval is 0.00128. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.-344C>T		5_prime_UTR_variant	Exon 1 of 33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.-344C>T		5_prime_UTR_variant	Exon 1 of 33	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000706 AC: 88 AN: 124600 AF XY: 0.000765

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000201

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.000526

GnomAD4 exome AF: 0.00108 AC: 1299 AN: 1205804 Hom.: 5 Cov.: 30 AF XY: 0.00110 AC XY: 651 AN XY: 590370

African (AFR) AF: 0.0000738 AC: 2 AN: 27110

American (AMR) AF: 0.000272 AC: 8 AN: 29410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18888

East Asian (EAS) AF: 0.00 AC: 0 AN: 19958

South Asian (SAS) AF: 0.00186 AC: 141 AN: 75712

European-Finnish (FIN) AF: 0.000229 AC: 4 AN: 17502

Middle Eastern (MID) AF: 0.000621 AC: 3 AN: 4830

European-Non Finnish (NFE) AF: 0.00116 AC: 1116 AN: 965800

Other (OTH) AF: 0.000537 AC: 25 AN: 46594

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74498

African (AFR) AF: 0.000144 AC: 6 AN: 41594

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4834

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000431

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Disorders of Intracellular Cobalamin Metabolism Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.8
DANN	Benign	0.76
PhyloP100		-0.051
PromoterAI		-0.076	Neutral
Mutation Taster		=99/1	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: rs575057926; hg19: chr1-236958660;