chr5-7876175-T-C

Variant names:

• chr5-7876175-T-C
• rs326121
• NM_002454.3:c.401+800T>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.401+800T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 93,044 control chromosomes in the GnomAD database, including 13,030 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 0.64 (13030 hom., cov: 32)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.71
• Publications: 8 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.401+800T>C		intron_variant	Intron 4 of 14	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.401+800T>C		intron_variant	Intron 4 of 14	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.635 AC: 58993 AN: 92926 Hom.: 12999 Cov.: 32

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.619

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.633

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

GnomAD4 genome AF: 0.635 AC: 59083 AN: 93044 Hom.: 13030 Cov.: 32 AF XY: 0.637 AC XY: 29347 AN XY: 46054

African (AFR) AF: 0.686 AC: 22760 AN: 33166

American (AMR) AF: 0.681 AC: 7904 AN: 11612

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 916 AN: 1622

East Asian (EAS) AF: 0.723 AC: 3174 AN: 4392

South Asian (SAS) AF: 0.643 AC: 2151 AN: 3346

European-Finnish (FIN) AF: 0.583 AC: 3164 AN: 5426

Middle Eastern (MID) AF: 0.608 AC: 101 AN: 166

European-Non Finnish (NFE) AF: 0.565 AC: 17887 AN: 31648

Other (OTH) AF: 0.634 AC: 809 AN: 1276

Alfa AF: 0.311 Hom.: 9481

Bravo AF: 0.411

Asia WGS AF: 0.560 AC: 1916 AN: 3426

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.23
DANN	Benign	0.24
PhyloP100		-4.7
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: rs326121; hg19: chr5-7876288;