1-236795553-C-T

Position:

• chr1-236795553-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000254.3(MTR):​c.-151C>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 0.0116 in 1,543,408 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (7 hom., cov: 33)
  • Exomes 𝑓: 0.012 (138 hom.)
• Consequence: MTR NM_000254.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0190

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-236795553-C-T is Benign according to our data. Variant chr1-236795553-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 296541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00808 (1231/152340) while in subpopulation NFE AF= 0.0122 (832/68028). AF 95% confidence interval is 0.0115. There are 7 homozygotes in gnomad4. There are 613 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.-151C>T		5_prime_UTR_variant	1/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.-151C>T		5_prime_UTR_variant	1/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1231 AN: 152222 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00735 AC: 1162 AN: 157988 Hom.: 5 AF XY: 0.00766 AC XY: 662 AN XY: 86422

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00596

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.0120 AC: 16624 AN: 1391068 Hom.: 138 Cov.: 31 AF XY: 0.0118 AC XY: 8122 AN XY: 688192

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00283

Gnomad4 ASJ exome AF: 0.00160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00646

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.00808 AC: 1231 AN: 152340 Hom.: 7 Cov.: 33 AF XY: 0.00823 AC XY: 613 AN XY: 74484

Gnomad4 AFR AF: 0.00252

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00409 Hom.: 1

Bravo AF: 0.00689

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	MTR: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs41305572; hg19: chr1-236958853;