rs142113735

Variant names:

• chr1-236895426-G-A
• rs142113735
• NM_000254.3:c.3474G>A

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.3474G>A​(p.Leu1158Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,604,632 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (36 hom.)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.10
• 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=-0.44).
• BP6: Variant 1-236895426-G-A is Benign according to our data. Variant chr1-236895426-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00492 (750/152330) while in subpopulation NFE AF = 0.00792 (539/68024). AF 95% confidence interval is 0.00737. There are 3 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.3474G>A	p.Leu1158Leu	synonymous	Exon 31 of 33	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.3321G>A	p.Leu1107Leu	synonymous	Exon 30 of 32	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.3285G>A	p.Leu1095Leu	synonymous	Exon 29 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.3474G>A	p.Leu1158Leu	synonymous	Exon 31 of 33	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.3321G>A	p.Leu1107Leu	synonymous	Exon 30 of 32	ENSP00000441845.1	Q99707-2
	MTR	ENST00000366576.3	TSL:1	c.2136G>A	p.Leu712Leu	synonymous	Exon 18 of 20	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 750 AN: 152212 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00792

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00480 AC: 1116 AN: 232384 AF XY: 0.00494

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.00766

Gnomad OTH exome AF: 0.00786

GnomAD4 exome AF: 0.00611 AC: 8868 AN: 1452302 Hom.: 36 Cov.: 29 AF XY: 0.00609 AC XY: 4392 AN XY: 721318

African (AFR) AF: 0.00105 AC: 35 AN: 33354

American (AMR) AF: 0.00274 AC: 120 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 133 AN: 25732

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.00180 AC: 152 AN: 84302

European-Finnish (FIN) AF: 0.00386 AC: 203 AN: 52650

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5758

European-Non Finnish (NFE) AF: 0.00711 AC: 7874 AN: 1107288

Other (OTH) AF: 0.00477 AC: 286 AN: 59992

GnomAD4 genome AF: 0.00492 AC: 750 AN: 152330 Hom.: 3 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74472

African (AFR) AF: 0.00111 AC: 46 AN: 41580

American (AMR) AF: 0.00595 AC: 91 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00792 AC: 539 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00612 Hom.: 4

Bravo AF: 0.00504

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	Methylcobalamin deficiency type cblG (1)
-	-	1	Methylcobalamin deficiency type cblG;C1866558:Neural tube defects, folate-sensitive (1)
-	-	1	MTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.3
DANN	Benign	0.72
PhyloP100		1.1
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: rs142113735; hg19: chr1-237058726;