rs955516

Variant names:

• chr1-236817204-T-A
• rs955516
• NM_000254.3:c.764+661T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000254.3(MTR):​c.764+661T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 151,996 control chromosomes in the GnomAD database, including 10,015 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (10015 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.764+661T>A		intron_variant	Intron 8 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.764+661T>A		intron_variant	Intron 8 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53068 AN: 151878 Hom.: 10013 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.348

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.349 AC: 53101 AN: 151996 Hom.: 10015 Cov.: 32 AF XY: 0.351 AC XY: 26051 AN XY: 74286

African (AFR) AF: 0.207 AC: 8581 AN: 41468

American (AMR) AF: 0.408 AC: 6224 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1062 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2088 AN: 5168

South Asian (SAS) AF: 0.304 AC: 1469 AN: 4826

European-Finnish (FIN) AF: 0.432 AC: 4543 AN: 10524

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27796 AN: 67954

Other (OTH) AF: 0.345 AC: 729 AN: 2114

Alfa AF: 0.375 Hom.: 1407

Bravo AF: 0.345

Asia WGS AF: 0.349 AC: 1213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.66
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: rs955516; hg19: chr1-236980504;