chr1-236892005-G-C

Variant names:

• chr1-236892005-G-C
• rs10802569
• NM_000254.3:c.3204+676G>C

Variant summary

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

The NM_000254.3(MTR):​c.3204+676G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 151,942 control chromosomes in the GnomAD database, including 33,554 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 0.66 (33554 hom., cov: 31)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.537
• Publications: 6 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3204+676G>C		intron_variant	Intron 29 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3204+676G>C		intron_variant	Intron 29 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1866+676G>C		intron_variant	Intron 16 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100383 AN: 151824 Hom.: 33513 Cov.: 31

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.611

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

GnomAD4 genome AF: 0.661 AC: 100478 AN: 151942 Hom.: 33554 Cov.: 31 AF XY: 0.663 AC XY: 49250 AN XY: 74266

African (AFR) AF: 0.747 AC: 30957 AN: 41416

American (AMR) AF: 0.638 AC: 9738 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1765 AN: 3470

East Asian (EAS) AF: 0.611 AC: 3152 AN: 5162

South Asian (SAS) AF: 0.705 AC: 3392 AN: 4812

European-Finnish (FIN) AF: 0.653 AC: 6894 AN: 10560

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42397 AN: 67954

Other (OTH) AF: 0.615 AC: 1297 AN: 2110

Alfa AF: 0.648 Hom.: 3983

Bravo AF: 0.662

Asia WGS AF: 0.666 AC: 2315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.45
DANN	Benign	0.37
PhyloP100		-0.54
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: rs10802569; hg19: chr1-237055305;