rs1770449

Variant names:

• chr1-236874861-T-C
• rs1770449
• NM_000254.3:c.2594+15T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-236874861-T-C
• chr1-236874861-T-G

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.2594+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,611,418 control chromosomes in the GnomAD database, including 99,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7105 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92293 hom.)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.157
• Publications: 22 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=-0.83).
• BP6: Variant 1-236874861-T-C is Benign according to our data. Variant chr1-236874861-T-C is described in ClinVar as Benign. ClinVar VariationId is 138288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.2594+15T>C		intron	N/A	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.2441+15T>C		intron	N/A	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.2406-5894T>C		intron	N/A	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.2594+15T>C		intron	N/A	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.2441+15T>C		intron	N/A	ENSP00000441845.1	Q99707-2
	MTR	ENST00000366576.3	TSL:1	c.1256+15T>C		intron	N/A	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41912 AN: 152062 Hom.: 7111 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.322 AC: 80647 AN: 250476 AF XY: 0.328

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.192

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.349 AC: 509353 AN: 1459238 Hom.: 92293 Cov.: 34 AF XY: 0.348 AC XY: 252911 AN XY: 725980

African (AFR) AF: 0.0649 AC: 2170 AN: 33426

American (AMR) AF: 0.311 AC: 13883 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 11996 AN: 26100

East Asian (EAS) AF: 0.161 AC: 6379 AN: 39592

South Asian (SAS) AF: 0.280 AC: 24110 AN: 86182

European-Finnish (FIN) AF: 0.343 AC: 18255 AN: 53298

Middle Eastern (MID) AF: 0.373 AC: 2152 AN: 5762

European-Non Finnish (NFE) AF: 0.369 AC: 409858 AN: 1109912

Other (OTH) AF: 0.341 AC: 20550 AN: 60278

GnomAD4 genome AF: 0.275 AC: 41900 AN: 152180 Hom.: 7105 Cov.: 32 AF XY: 0.274 AC XY: 20417 AN XY: 74396

African (AFR) AF: 0.0815 AC: 3388 AN: 41568

American (AMR) AF: 0.323 AC: 4934 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1617 AN: 3468

East Asian (EAS) AF: 0.187 AC: 967 AN: 5170

South Asian (SAS) AF: 0.273 AC: 1319 AN: 4826

European-Finnish (FIN) AF: 0.348 AC: 3677 AN: 10580

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.369 AC: 25050 AN: 67962

Other (OTH) AF: 0.311 AC: 657 AN: 2112

Alfa AF: 0.306 Hom.: 6544

Bravo AF: 0.264

Asia WGS AF: 0.228 AC: 795 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Methylcobalamin deficiency type cblG (2)
-	-	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	-0.83
CADD	Benign	1.9
DANN	Benign	0.52
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1770449; hg19: chr1-237038161; COSMIC: COSV63964725;