Genetic Variant MTR:c.502+229G>A (chr1-236810824-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000254.3(MTR):c.502+229G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 152,058 control chromosomes in the GnomAD database, including 8,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.31 ( 8974 hom., cov: 32)

Consequence

MTR
NM_000254.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.23

Publications

5 publications found

Variant links:

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

MTR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-236810824-G-A is Benign according to our data. Variant chr1-236810824-G-A is described in ClinVar as Benign. ClinVar VariationId is 1252634.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.399 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTR	NM_000254.3	MANE Select	c.502+229G>A	intron	N/A	NP_000245.2	Q99707-1
MTR	NM_001291939.1		c.502+229G>A	intron	N/A	NP_001278868.1	Q99707-2
MTR	NM_001410942.1		c.502+229G>A	intron	N/A	NP_001397871.1	A0A7P0TAJ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTR	ENST00000366577.10	TSL:1 MANE Select	c.502+229G>A	intron	N/A	ENSP00000355536.5	Q99707-1
MTR	ENST00000535889.6	TSL:1	c.502+229G>A	intron	N/A	ENSP00000441845.1	Q99707-2
MTR	ENST00000681102.1		c.502+229G>A	intron	N/A	ENSP00000505600.1	A0A7P0T9G7

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47392

AN:

151940

Hom.:

8973

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0904

Gnomad AMI

AF:

0.562

Gnomad AMR

AF:

0.388

Gnomad ASJ

AF:

0.295

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.426

Gnomad MID

AF:

0.318

Gnomad NFE

AF:

0.403

Gnomad OTH

AF:

0.327

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

GnomAD4 genome

AF:

0.312

AC:

47409

AN:

152058

Hom.:

8974

Cov.:

AF XY:

0.314

AC XY:

23351

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0903

AC:

3747

AN:

41514

American (AMR)

AF:

0.388

AC:

5936

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.295

AC:

1023

AN:

3468

East Asian (EAS)

AF:

0.401

AC:

2077

AN:

5186

South Asian (SAS)

AF:

0.302

AC:

1454

AN:

4812

European-Finnish (FIN)

AF:

0.426

AC:

4494

AN:

10540

Middle Eastern (MID)

AF:

0.322

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.403

AC:

27392

AN:

67944

Other (OTH)

AF:

0.323

AC:

681

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1568

3136

4705

6273

7841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.362

Hom.:

2529

Bravo

AF:

0.303

Asia WGS

AF:

0.337

AC:

1170

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.096

(source)

DANN

Benign

0.39

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over