rs162049

Variant names:

• chr5-7893008-G-A
• rs162049
• NM_002454.3:c.1557+95G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002454.3(MTRR):​c.1557+95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 1,360,854 control chromosomes in the GnomAD database, including 424,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48955 hom., cov: 34)
  • Exomes 𝑓: 0.79 (375457 hom.)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.84
• Publications: 17 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-7893008-G-A is Benign according to our data. Variant chr5-7893008-G-A is described in ClinVar as Benign. ClinVar VariationId is 1230987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.1557+95G>A		intron_variant	Intron 11 of 14	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.1557+95G>A		intron_variant	Intron 11 of 14	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.797 AC: 121284 AN: 152150 Hom.: 48904 Cov.: 34

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.781

GnomAD4 exome AF: 0.785 AC: 948746 AN: 1208586 Hom.: 375457 Cov.: 17 AF XY: 0.784 AC XY: 473774 AN XY: 604466

African (AFR) AF: 0.877 AC: 23881 AN: 27236

American (AMR) AF: 0.704 AC: 23509 AN: 33392

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 17995 AN: 23642

East Asian (EAS) AF: 0.468 AC: 16338 AN: 34904

South Asian (SAS) AF: 0.763 AC: 55863 AN: 73238

European-Finnish (FIN) AF: 0.748 AC: 34595 AN: 46272

Middle Eastern (MID) AF: 0.785 AC: 4154 AN: 5290

European-Non Finnish (NFE) AF: 0.802 AC: 732086 AN: 912850

Other (OTH) AF: 0.779 AC: 40325 AN: 51762

GnomAD4 genome AF: 0.797 AC: 121401 AN: 152268 Hom.: 48955 Cov.: 34 AF XY: 0.793 AC XY: 58997 AN XY: 74442

African (AFR) AF: 0.872 AC: 36261 AN: 41564

American (AMR) AF: 0.762 AC: 11654 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2689 AN: 3470

East Asian (EAS) AF: 0.487 AC: 2519 AN: 5176

South Asian (SAS) AF: 0.765 AC: 3688 AN: 4822

European-Finnish (FIN) AF: 0.747 AC: 7911 AN: 10592

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.795 AC: 54074 AN: 68026

Other (OTH) AF: 0.781 AC: 1650 AN: 2112

Alfa AF: 0.799 Hom.: 71523

Bravo AF: 0.799

Asia WGS AF: 0.626 AC: 2177 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.015
DANN	Benign	0.23
PhyloP100		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs162049; hg19: chr5-7893121;