1-236795698-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000254.3(MTR):c.-6G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,124 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: MTR NM_000254.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00124 (189/152390) while in subpopulation NFE AF= 0.00226 (154/68034). AF 95% confidence interval is 0.00197. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.-6G>C		5_prime_UTR_variant	1/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.-6G>C		5_prime_UTR_variant	1/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 188 AN: 152272 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000828 AC: 208 AN: 251156 Hom.: 0 AF XY: 0.000898 AC XY: 122 AN XY: 135890

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00169 AC: 2468 AN: 1461734 Hom.: 7 Cov.: 31 AF XY: 0.00162 AC XY: 1179 AN XY: 727162

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.000657

Gnomad4 NFE exome AF: 0.00201

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152390 Hom.: 0 Cov.: 33 AF XY: 0.00106 AC XY: 79 AN XY: 74528

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00110

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00154

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	Nucleotide substitution has no predicted effect on splicing and is not conserved across species; Has not been previously published as pathogenic or benign to our knowledge; In the absence of RNA/functional studies, the actual effect of this sequence change is unknown -

Disorders of Intracellular Cobalamin Metabolism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.2
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

LitVar

Other links and lift over

dbSNP: rs183719210; hg19: chr1-236958998;