5-7878066-C-G

Variant names:

• chr5-7878066-C-G
• rs1532268
• NM_002454.3:c.524C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002454.3(MTRR):​c.524C>G​(p.Ser175Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S175P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070283085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.524C>G	p.Ser175Trp	missense_variant	Exon 5 of 15	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.524C>G	p.Ser175Trp	missense_variant	Exon 5 of 15	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.080
DANN	Benign	0.78
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.30	T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N;.
PhyloP100		-2.4
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.046	D;D
Vest4		0.20
MutPred		0.42		Loss of disorder (P = 5e-04);.;
MVP		0.23
MPC		0.059
ClinPred		0.088	T
GERP RS		-11
Varity_R		0.045
gMVP		0.33
Mutation Taster		=96/4	polymorphism

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: rs1532268; hg19: chr5-7878179;