rs148909799

chr5-7899943-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002454.3(MTRR):c.1982A>G(p.His661Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,614,224 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H661H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.67

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00992918).
• BP6: Variant 5-7899943-A-G is Benign according to our data. Variant chr5-7899943-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203841.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=4}. Variant chr5-7899943-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (293/152360) while in subpopulation NFE AF= 0.00345 (235/68032). AF 95% confidence interval is 0.00309. There are 1 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.1982A>G	p.His661Arg	missense_variant	15/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.1982A>G	p.His661Arg	missense_variant	15/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 293 AN: 152242 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000723

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00187 AC: 471 AN: 251296 Hom.: 2 AF XY: 0.00194 AC XY: 264 AN XY: 135822

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00323 AC: 4719 AN: 1461864 Hom.: 9 Cov.: 31 AF XY: 0.00320 AC XY: 2330 AN XY: 727232

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.00385

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152360 Hom.: 1 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74506

Gnomad4 AFR AF: 0.000721

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00345

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00289 Hom.: 3

Bravo AF: 0.00186

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MTRR: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 25, 2021	The MTRR c.1982A>G; p.His661Arg variant (rs148909799), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is reported as uncertain significance/likely benign in ClinVar (Variation ID: 203841), and is found in the general population with an overall allele frequency of 0.19% (523/277,022 alleles, including 2 homozygotes) in the Genome Aggregation Database. The histidine at codon 661 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site, however without mRNA analysis it is unclear if this variant impacts splicing. Due to limited information, the clinical significance of the p.His661Arg variant is uncertain at this time. -

Disorders of Intracellular Cobalamin Metabolism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Methylcobalamin deficiency type cblE Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

MTRR-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Benign	0.88
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0099	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.18	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.19
Sift	Benign	0.97	T;T
Sift4G	Benign	0.52	T;T
Vest4		0.13
MVP		0.70
MPC		0.064
ClinPred		0.018	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148909799; hg19: chr5-7900056; COSMIC: COSV99241642; COSMIC: COSV99241642;