Genetic Variant NM_000254.3:c.2775+43G>A (chr1-236885262-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000254.3(MTR):c.2775+43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,181,190 control chromosomes in the GnomAD database, including 258,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 40163 hom., cov: 32)

Exomes 𝑓: 0.65 ( 218448 hom. )

Consequence

MTR
NM_000254.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.28

Publications

11 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-236885262-G-A is Benign according to our data. Variant chr1-236885262-G-A is described in ClinVar as Benign. ClinVar VariationId is 1258762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.886 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.2775+43G>A	intron	N/A	NP_000245.2	Q99707-1
MTR	NM_001291939.1		c.2622+43G>A	intron	N/A	NP_001278868.1	Q99707-2
MTR	NM_001410942.1		c.2586+43G>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.2775+43G>A	intron	N/A	ENSP00000355536.5	Q99707-1
MTR	ENST00000535889.6	TSL:1	c.2622+43G>A	intron	N/A	ENSP00000441845.1	Q99707-2
MTR	ENST00000366576.3	TSL:1	c.1437+43G>A	intron	N/A	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes

AF:

0.716

AC:

108810

AN:

151946

Hom.:

40112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.894

Gnomad AMI

AF:

0.802

Gnomad AMR

AF:

0.672

Gnomad ASJ

AF:

0.511

Gnomad EAS

AF:

0.814

Gnomad SAS

AF:

0.726

Gnomad FIN

AF:

0.653

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.631

Gnomad OTH

AF:

0.672

GnomAD2 exomes

AF:

0.673

AC:

163782

AN:

243312

AF XY:

0.667

show subpopulations

Gnomad AFR exome

AF:

0.906

Gnomad AMR exome

AF:

0.683

Gnomad ASJ exome

AF:

0.512

Gnomad EAS exome

AF:

0.808

Gnomad FIN exome

AF:

0.652

Gnomad NFE exome

AF:

0.623

Gnomad OTH exome

AF:

0.651

GnomAD4 exome

AF:

0.646

AC:

665139

AN:

1029128

Hom.:

218448

Cov.:

AF XY:

0.648

AC XY:

344219

AN XY:

531366

show subpopulations

African (AFR)

AF:

0.904

AC:

22349

AN:

24726

American (AMR)

AF:

0.686

AC:

30136

AN:

43914

Ashkenazi Jewish (ASJ)

AF:

0.513

AC:

12053

AN:

23518

East Asian (EAS)

AF:

0.842

AC:

31668

AN:

37624

South Asian (SAS)

AF:

0.716

AC:

54929

AN:

76738

European-Finnish (FIN)

AF:

0.656

AC:

33792

AN:

51474

Middle Eastern (MID)

AF:

0.592

AC:

2593

AN:

4378

European-Non Finnish (NFE)

AF:

0.621

AC:

447761

AN:

720746

Other (OTH)

AF:

0.649

AC:

29858

AN:

46010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

11602

23205

34807

46410

58012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9606

19212

28818

38424

48030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.716

AC:

108923

AN:

152062

Hom.:

40163

Cov.:

AF XY:

0.717

AC XY:

53293

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.894

AC:

37120

AN:

41530

American (AMR)

AF:

0.672

AC:

10276

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.511

AC:

1774

AN:

3472

East Asian (EAS)

AF:

0.814

AC:

4212

AN:

5172

South Asian (SAS)

AF:

0.726

AC:

3487

AN:

4804

European-Finnish (FIN)

AF:

0.653

AC:

6873

AN:

10532

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.631

AC:

42856

AN:

67958

Other (OTH)

AF:

0.675

AC:

1422

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1501

3002

4503

6004

7505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<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:

0.663

Hom.:

9041

Bravo

AF:

0.726

Asia WGS

AF:

0.766

AC:

2658

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.069

(source)

DANN

Benign

0.16

PhyloP100

-1.3

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over