dbSNP rs17243407: MTRR:n.392-3943G>A (chr5-7858008-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000502509.5(MTRR):n.392-3943G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,160 control chromosomes in the GnomAD database, including 1,827 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 0.13 ( 1827 hom., cov: 32)

Consequence

MTRR
ENST00000502509.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0350

Publications

5 publications found

Variant links:

Genes affected

MTRR (HGNC:7473): (5-methyltetrahydrofolate-homocysteine methyltransferase reductase) This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

MTRR Gene-Disease associations (from GenCC):

methylcobalamin deficiency type cblE
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

MTRR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
MTRR	XM_024446064.2 link	c.-133+1116G>A	intron_variant	Intron 2 of 16	XP_024301832.1
MTRR	XM_047417233.1 link	c.-452+1116G>A	intron_variant	Intron 2 of 17	XP_047273189.1
MTRR	XM_047417234.1 link	c.-132-3943G>A	intron_variant	Intron 1 of 15	XP_047273190.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
MTRR	ENST00000502509.5 link	n.392-3943G>A	intron_variant	Intron 1 of 3	3
MTRR	ENST00000507837.5 link	n.506+1116G>A	intron_variant	Intron 2 of 2	4
MTRR	ENST00000511639.1 link	n.492+1116G>A	intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20403

AN:

152042

Hom.:

1827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0366

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0842

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.111

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

GnomAD4 genome

AF:

0.134

AC:

20406

AN:

152160

Hom.:

1827

Cov.:

AF XY:

0.132

AC XY:

9803

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0365

AC:

1518

AN:

41534

American (AMR)

AF:

0.103

AC:

1570

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.184

AC:

638

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5182

South Asian (SAS)

AF:

0.0846

AC:

408

AN:

4820

European-Finnish (FIN)

AF:

0.189

AC:

1995

AN:

10576

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.203

AC:

13780

AN:

67976

Other (OTH)

AF:

0.110

AC:

233

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

894

1788

2682

3576

4470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.173

Hom.:

4105

Bravo

AF:

0.123

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.85

(source)

DANN

Benign

0.78

PhyloP100

-0.035

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over