rs146019467

Variant names:

• chr1-236824212-C-T
• rs146019467
• NM_000254.3:c.858C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000254.3(MTR):​c.858C>T​(p.Pro286Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,612,330 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (56 hom.)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0530
• Publications: 0 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 1-236824212-C-T is Benign according to our data. Variant chr1-236824212-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 199000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.053 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00541 (823/152112) while in subpopulation NFE AF = 0.00693 (471/67988). AF 95% confidence interval is 0.00641. There are 5 homozygotes in GnomAd4. There are 456 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.858C>T	p.Pro286Pro	synonymous	Exon 9 of 33	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.858C>T	p.Pro286Pro	synonymous	Exon 9 of 32	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.858C>T	p.Pro286Pro	synonymous	Exon 9 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.858C>T	p.Pro286Pro	synonymous	Exon 9 of 33	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.858C>T	p.Pro286Pro	synonymous	Exon 9 of 32	ENSP00000441845.1	Q99707-2
	MTR	ENST00000681102.1		c.858C>T	p.Pro286Pro	synonymous	Exon 9 of 32	ENSP00000505600.1	A0A7P0T9G7

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 823 AN: 151994 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00693

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00596 AC: 1499 AN: 251448 AF XY: 0.00584

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00571 AC: 8336 AN: 1460218 Hom.: 56 Cov.: 30 AF XY: 0.00570 AC XY: 4145 AN XY: 726566

African (AFR) AF: 0.000837 AC: 28 AN: 33454

American (AMR) AF: 0.00268 AC: 120 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00128 AC: 110 AN: 86214

European-Finnish (FIN) AF: 0.0245 AC: 1309 AN: 53414

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00583 AC: 6471 AN: 1110490

Other (OTH) AF: 0.00451 AC: 272 AN: 60342

GnomAD4 genome AF: 0.00541 AC: 823 AN: 152112 Hom.: 5 Cov.: 31 AF XY: 0.00613 AC XY: 456 AN XY: 74352

African (AFR) AF: 0.00118 AC: 49 AN: 41490

American (AMR) AF: 0.00124 AC: 19 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.0252 AC: 266 AN: 10564

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

European-Non Finnish (NFE) AF: 0.00693 AC: 471 AN: 67988

Other (OTH) AF: 0.00570 AC: 12 AN: 2104

Alfa AF: 0.00578 Hom.: 0

Bravo AF: 0.00323

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00545

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	Methylcobalamin deficiency type cblG (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	7.7
DANN	Benign	0.72
PhyloP100		-0.053
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs146019467; hg19: chr1-236987512; COSMIC: COSV63968254; COSMIC: COSV63968254;