NM_000254.3:c.-321C>G

Variant names:

• chr1-236795383-C-G
• rs187186973
• NM_000254.3:c.-321C>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.-321C>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 0.000433 in 1,403,430 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (5 hom.)
• Consequence: MTR NM_000254.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0770
• 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-236795383-C-G is Benign according to our data. Variant chr1-236795383-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 296536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000899 (137/152354) while in subpopulation EAS AF = 0.0166 (86/5172). AF 95% confidence interval is 0.0138. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.-321C>G		5_prime_UTR	Exon 1 of 33	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.-321C>G		5_prime_UTR	Exon 1 of 32	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.-321C>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.-321C>G		5_prime_UTR	Exon 1 of 33	ENSP00000355536.5	Q99707-1
	MTR	ENST00000961801.1		c.-321C>G		5_prime_UTR	Exon 1 of 31	ENSP00000631860.1
	MTR	ENST00000905140.1		c.-321C>G		5_prime_UTR	Exon 1 of 32	ENSP00000575199.1

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00195 AC: 252 AN: 129128 AF XY: 0.00168

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.0000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0228

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000203

Gnomad OTH exome AF: 0.000760

GnomAD4 exome AF: 0.000376 AC: 470 AN: 1251076 Hom.: 5 Cov.: 30 AF XY: 0.000350 AC XY: 215 AN XY: 614492

African (AFR) AF: 0.000387 AC: 11 AN: 28458

American (AMR) AF: 0.0000318 AC: 1 AN: 31414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20842

East Asian (EAS) AF: 0.0139 AC: 326 AN: 23536

South Asian (SAS) AF: 0.0000650 AC: 5 AN: 76938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5058

European-Non Finnish (NFE) AF: 0.00000603 AC: 6 AN: 994330

Other (OTH) AF: 0.00244 AC: 121 AN: 49660

GnomAD4 genome AF: 0.000899 AC: 137 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74494

African (AFR) AF: 0.000697 AC: 29 AN: 41596

American (AMR) AF: 0.000653 AC: 10 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0166 AC: 86 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.000427 Hom.: 1

Bravo AF: 0.00100

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.5
DANN	Benign	0.62
PhyloP100		0.077
PromoterAI		-0.085	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=299/1	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: rs187186973; hg19: chr1-236958683;