1-236795503-C-G

Variant names:

• chr1-236795503-C-G
• rs111840642
• NM_000254.3:c.-201C>G

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.-201C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,521,628 control chromosomes in the GnomAD database, including 301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (35 hom., cov: 33)
  • Exomes 𝑓: 0.018 (266 hom.)
• Consequence: MTR NM_000254.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.48

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=-0.8).
• BP6: Variant 1-236795503-C-G is Benign according to our data. Variant chr1-236795503-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 296538.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 = 0.0147 (2242/152338) while in subpopulation NFE AF= 0.0232 (1579/68020). AF 95% confidence interval is 0.0223. There are 35 homozygotes in gnomad4. There are 1056 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.-201C>G		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	c.-201C>G		5_prime_UTR_variant	Exon 1 of 33	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2241 AN: 152220 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0142 AC: 1926 AN: 135266 Hom.: 19 AF XY: 0.0139 AC XY: 1019 AN XY: 73468

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.0000930

Gnomad SAS exome AF: 0.00357

Gnomad FIN exome AF: 0.00848

Gnomad NFE exome AF: 0.0226

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0180 AC: 24613 AN: 1369290 Hom.: 266 Cov.: 31 AF XY: 0.0176 AC XY: 11887 AN XY: 675526

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.0000571

Gnomad4 SAS exome AF: 0.00287

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.0204

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0147 AC: 2242 AN: 152338 Hom.: 35 Cov.: 33 AF XY: 0.0142 AC XY: 1056 AN XY: 74492

Gnomad4 AFR AF: 0.00305

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0191 Hom.: 8

Bravo AF: 0.0146

Asia WGS AF: 0.00202 AC: 7 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.80
CADD	Benign	1.9
DANN	Benign	0.64
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: rs111840642; hg19: chr1-236958803; COSMIC: COSV63969509; COSMIC: COSV63969509;