rs327592

Variant names:

• chr5-7899731-A-G
• rs327592
• NM_002454.3:c.1953-183A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002454.3(MTRR):​c.1953-183A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,160 control chromosomes in the GnomAD database, including 4,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (4547 hom., cov: 32)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.463
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-7899731-A-G is Benign according to our data. Variant chr5-7899731-A-G is described in ClinVar as Benign. ClinVar VariationId is 1236678.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.1953-183A>G		intron_variant	Intron 14 of 14	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.1953-183A>G		intron_variant	Intron 14 of 14	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31343 AN: 152042 Hom.: 4533 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0683

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.206 AC: 31407 AN: 152160 Hom.: 4547 Cov.: 32 AF XY: 0.204 AC XY: 15201 AN XY: 74402

African (AFR) AF: 0.381 AC: 15807 AN: 41472

American (AMR) AF: 0.296 AC: 4528 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 606 AN: 3470

East Asian (EAS) AF: 0.173 AC: 894 AN: 5168

South Asian (SAS) AF: 0.142 AC: 686 AN: 4820

European-Finnish (FIN) AF: 0.0683 AC: 725 AN: 10618

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7649 AN: 68004

Other (OTH) AF: 0.200 AC: 423 AN: 2110

Alfa AF: 0.166 Hom.: 402

Bravo AF: 0.233

Asia WGS AF: 0.158 AC: 550 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.46
PhyloP100		-0.46
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: rs327592; hg19: chr5-7899844; COSMIC: COSV52943366; COSMIC: COSV52943366;