1-236873957-C-A

Variant names:

• chr1-236873957-C-A
• rs10495387
• NM_000254.3:c.2473+117C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000254.3(MTR):​c.2473+117C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 997,328 control chromosomes in the GnomAD database, including 1,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (773 hom., cov: 32)
  • Exomes 𝑓: 0.032 (967 hom.)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• Publications: 5 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-236873957-C-A is Benign according to our data. Variant chr1-236873957-C-A is described in ClinVar as Benign. ClinVar VariationId is 1229463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.2473+117C>A		intron	N/A	NP_000245.2
	MTR	NM_001291939.1		c.2320+117C>A		intron	N/A	NP_001278868.1
	MTR	NM_001410942.1		c.2406-6798C>A		intron	N/A	NP_001397871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.2473+117C>A		intron	N/A	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.2320+117C>A		intron	N/A	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.1135+117C>A		intron	N/A	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10903 AN: 152048 Hom.: 770 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.0542

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0666

GnomAD4 exome AF: 0.0318 AC: 26916 AN: 845162 Hom.: 967 AF XY: 0.0332 AC XY: 14595 AN XY: 439080

African (AFR) AF: 0.191 AC: 4062 AN: 21252

American (AMR) AF: 0.0356 AC: 1385 AN: 38880

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 226 AN: 21660

East Asian (EAS) AF: 0.0584 AC: 2051 AN: 35100

South Asian (SAS) AF: 0.0769 AC: 5371 AN: 69868

European-Finnish (FIN) AF: 0.0169 AC: 759 AN: 44926

Middle Eastern (MID) AF: 0.0553 AC: 254 AN: 4594

European-Non Finnish (NFE) AF: 0.0198 AC: 11259 AN: 568946

Other (OTH) AF: 0.0388 AC: 1549 AN: 39936

GnomAD4 genome AF: 0.0718 AC: 10923 AN: 152166 Hom.: 773 Cov.: 32 AF XY: 0.0714 AC XY: 5316 AN XY: 74408

African (AFR) AF: 0.185 AC: 7675 AN: 41462

American (AMR) AF: 0.0461 AC: 705 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.0544 AC: 281 AN: 5170

South Asian (SAS) AF: 0.0896 AC: 432 AN: 4820

European-Finnish (FIN) AF: 0.0166 AC: 176 AN: 10614

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1439 AN: 68012

Other (OTH) AF: 0.0664 AC: 140 AN: 2110

Alfa AF: 0.0405 Hom.: 125

Bravo AF: 0.0791

Asia WGS AF: 0.0830 AC: 289 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.31
DANN	Benign	0.55
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs10495387; hg19: chr1-237037257;