NM_000254.3:c.-201C>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.005).
• BP6: Variant 1-236795503-C-G is Benign according to our data. Variant chr1-236795503-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.-201C>G		5_prime_UTR	Exon 1 of 33	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.-201C>G		5_prime_UTR	Exon 1 of 32	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.-201C>G		5_prime_UTR	Exon 1 of 31	NP_001397871.1	A0A7P0TAJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.-201C>G		5_prime_UTR	Exon 1 of 33	ENSP00000355536.5	Q99707-1
	MTR	ENST00000961801.1		c.-201C>G		5_prime_UTR	Exon 1 of 31	ENSP00000631860.1
	MTR	ENST00000905140.1		c.-201C>G		5_prime_UTR	Exon 1 of 32	ENSP00000575199.1

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

GnomAD2 exomes AF: 0.0142 AC: 1926 AN: 135266 AF XY: 0.0139

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 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

African (AFR) AF: 0.00311 AC: 97 AN: 31214

American (AMR) AF: 0.0136 AC: 480 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 553 AN: 24712

East Asian (EAS) AF: 0.0000571 AC: 2 AN: 35014

South Asian (SAS) AF: 0.00287 AC: 225 AN: 78378

European-Finnish (FIN) AF: 0.0102 AC: 336 AN: 32784

Middle Eastern (MID) AF: 0.0251 AC: 141 AN: 5614

European-Non Finnish (NFE) AF: 0.0204 AC: 21804 AN: 1069414

Other (OTH) AF: 0.0171 AC: 975 AN: 56968

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

African (AFR) AF: 0.00305 AC: 127 AN: 41592

American (AMR) AF: 0.0190 AC: 291 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1579 AN: 68020

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0191 Hom.: 8

Bravo AF: 0.0146

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.64
PhyloP100		-1.5
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	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: rs111840642; hg19: chr1-236958803; COSMIC: COSV63969509; COSMIC: COSV63969509;