dbSNP rs41530146: MTR:c.3599-10C>A (chr1-236896996-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000254.3(MTR):c.3599-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,601,734 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 36 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 57 hom. )

Consequence

MTR
NM_000254.3 intron

Scores

Splicing: ADA: 0.0001485

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.132

Publications

3 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=-0.8).

BP6

Variant 1-236896996-C-A is Benign according to our data. Variant chr1-236896996-C-A is described in ClinVar as Benign. ClinVar VariationId is 296583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1739/152296) while in subpopulation AFR AF = 0.0338 (1405/41548). AF 95% confidence interval is 0.0323. There are 36 homozygotes in GnomAd4. There are 829 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

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.3599-10C>A	intron	N/A	NP_000245.2	Q99707-1
MTR	NM_001291939.1		c.3446-10C>A	intron	N/A	NP_001278868.1	Q99707-2
MTR	NM_001410942.1		c.3410-10C>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.3599-10C>A	intron	N/A	ENSP00000355536.5	Q99707-1
MTR	ENST00000535889.6	TSL:1	c.3446-10C>A	intron	N/A	ENSP00000441845.1	Q99707-2
MTR	ENST00000366576.3	TSL:1	c.2261-10C>A	intron	N/A	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1740

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00496

AC:

1248

AN:

251402

AF XY:

0.00432

show subpopulations

Gnomad AFR exome

AF:

0.0365

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.0252

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00273

AC:

3964

AN:

1449438

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

1878

AN XY:

722106

show subpopulations

African (AFR)

AF:

0.0376

AC:

1249

AN:

33188

American (AMR)

AF:

0.00349

AC:

156

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

659

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00186

AC:

160

AN:

85980

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.0357

AC:

205

AN:

5742

European-Non Finnish (NFE)

AF:

0.00104

AC:

1149

AN:

1100788

Other (OTH)

AF:

0.00642

AC:

385

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

191

382

572

763

954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0114

AC:

1739

AN:

152296

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

829

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0338

AC:

1405

AN:

41548

American (AMR)

AF:

0.00719

AC:

110

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

68022

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

171

257

342

428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00527

Hom.:

Bravo

AF:

0.0134

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Disorders of Intracellular Cobalamin Metabolism (1)

Methylcobalamin deficiency type cblG (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.6

(source)

DANN

Benign

0.56

PhyloP100

0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.048

SpliceAI score (max)

0.12

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