NM_000254.3:c.*1684C>T

Variant names:

• chr1-236899328-C-T
• rs1804742
• NM_000254.3:c.*1684C>T

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.*1684C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,040 control chromosomes in the GnomAD database, including 3,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3423 hom., cov: 32)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: MTR NM_000254.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0310
• Publications: 10 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=-0.89).
• BP6: Variant 1-236899328-C-T is Benign according to our data. Variant chr1-236899328-C-T is described in ClinVar as Benign. ClinVar VariationId is 296618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.262 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.*1684C>T		3_prime_UTR	Exon 33 of 33	NP_000245.2
	MTR	NM_001291939.1		c.*1684C>T		3_prime_UTR	Exon 32 of 32	NP_001278868.1
	MTR	NM_001410942.1		c.*1684C>T		3_prime_UTR	Exon 31 of 31	NP_001397871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.*1684C>T		3_prime_UTR	Exon 33 of 33	ENSP00000355536.5
	MTR	ENST00000366576.3	TSL:1	c.*1684C>T		3_prime_UTR	Exon 20 of 20	ENSP00000355535.3
	MTR	ENST00000961801.1		c.*1684C>T		3_prime_UTR	Exon 31 of 31	ENSP00000631860.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31193 AN: 151904 Hom.: 3412 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.173

GnomAD4 exome AF: 0.0556 AC: 1 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.100 AC XY: 1 AN XY: 10

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.100 AC: 1 AN: 10

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.205 AC: 31239 AN: 152022 Hom.: 3423 Cov.: 32 AF XY: 0.208 AC XY: 15431 AN XY: 74300

African (AFR) AF: 0.261 AC: 10807 AN: 41472

American (AMR) AF: 0.170 AC: 2590 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3468

East Asian (EAS) AF: 0.117 AC: 603 AN: 5174

South Asian (SAS) AF: 0.274 AC: 1319 AN: 4816

European-Finnish (FIN) AF: 0.212 AC: 2233 AN: 10550

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.184 AC: 12522 AN: 67974

Other (OTH) AF: 0.181 AC: 382 AN: 2112

Alfa AF: 0.184 Hom.: 3363

Bravo AF: 0.200

Asia WGS AF: 0.205 AC: 713 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.89
CADD	Benign	1.7
DANN	Benign	0.55
PhyloP100		-0.031
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: rs1804742; hg19: chr1-237062628;