ENST00000502509.5:n.392-3943G>A

Variant names:

• chr5-7858008-G-A
• rs17243407
• ENST00000502509.5:n.392-3943G>A

Variant summary

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

The ENST00000502509.5(MTRR):​n.392-3943G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,160 control chromosomes in the GnomAD database, including 1,827 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 0.13 (1827 hom., cov: 32)
• Consequence: MTRR ENST00000502509.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0350
• Publications: 5 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	XM_024446064.2	c.-133+1116G>A		intron_variant	Intron 2 of 16		XP_024301832.1
MTRR	XM_047417233.1	c.-452+1116G>A		intron_variant	Intron 2 of 17		XP_047273189.1
MTRR	XM_047417234.1	c.-132-3943G>A		intron_variant	Intron 1 of 15		XP_047273190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000502509.5	n.392-3943G>A		intron_variant	Intron 1 of 3	3
MTRR	ENST00000507837.5	n.506+1116G>A		intron_variant	Intron 2 of 2	4
MTRR	ENST00000511639.1	n.492+1116G>A		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20403 AN: 152042 Hom.: 1827 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0842

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.134 AC: 20406 AN: 152160 Hom.: 1827 Cov.: 32 AF XY: 0.132 AC XY: 9803 AN XY: 74370

African (AFR) AF: 0.0365 AC: 1518 AN: 41534

American (AMR) AF: 0.103 AC: 1570 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5182

South Asian (SAS) AF: 0.0846 AC: 408 AN: 4820

European-Finnish (FIN) AF: 0.189 AC: 1995 AN: 10576

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13780 AN: 67976

Other (OTH) AF: 0.110 AC: 233 AN: 2116

Alfa AF: 0.173 Hom.: 4105

Bravo AF: 0.123

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.85
DANN	Benign	0.78
PhyloP100		-0.035

Splicing

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

Other links and lift over

dbSNP: rs17243407; hg19: chr5-7858121;