rs162031

Variant names:

• chr5-7880174-T-C
• rs162031
• NM_002454.3:c.780+1852T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002454.3(MTRR):​c.780+1852T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 152,200 control chromosomes in the GnomAD database, including 49,259 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 0.80 (49259 hom., cov: 33)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.349
• Publications: 24 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.780+1852T>C		intron_variant	Intron 5 of 14	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.780+1852T>C		intron_variant	Intron 5 of 14	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121646 AN: 152082 Hom.: 49206 Cov.: 33

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.746

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.782

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

GnomAD4 genome AF: 0.800 AC: 121764 AN: 152200 Hom.: 49259 Cov.: 33 AF XY: 0.795 AC XY: 59137 AN XY: 74390

African (AFR) AF: 0.883 AC: 36692 AN: 41556

American (AMR) AF: 0.763 AC: 11666 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2685 AN: 3472

East Asian (EAS) AF: 0.512 AC: 2644 AN: 5160

South Asian (SAS) AF: 0.765 AC: 3693 AN: 4828

European-Finnish (FIN) AF: 0.746 AC: 7884 AN: 10570

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.793 AC: 53891 AN: 68000

Other (OTH) AF: 0.782 AC: 1652 AN: 2112

Alfa AF: 0.788 Hom.: 131124

Bravo AF: 0.802

Asia WGS AF: 0.633 AC: 2201 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.50
PhyloP100		-0.35
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: rs162031; hg19: chr5-7880287;