rs10520873

Variant names:

• chr5-7901117-T-C
• rs10520873
• ENST00000264668.6:c.*1059T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000264668.6(MTRR):​c.*1059T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,120 control chromosomes in the GnomAD database, including 4,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4397 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: MTRR ENST00000264668.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.144
• Publications: 15 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-7901117-T-C is Benign according to our data. Variant chr5-7901117-T-C is described in ClinVar as Benign. ClinVar VariationId is 354381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264668.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	NM_002454.3	MANE Select	c.*1059T>C		downstream_gene	N/A	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.*1059T>C		downstream_gene	N/A	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.*1059T>C		downstream_gene	N/A	NP_001351370.1	Q9UBK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	ENST00000264668.6	TSL:1	c.*1059T>C		3_prime_UTR	Exon 15 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000869931.1		c.*1059T>C		splice_region	Exon 15 of 15	ENSP00000539990.1
	MTRR	ENST00000941611.1		c.*1059T>C		splice_region	Exon 16 of 16	ENSP00000611670.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33318 AN: 152002 Hom.: 4399 Cov.: 33

Gnomad AFR AF: 0.0794

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.218

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.219 AC: 33304 AN: 152120 Hom.: 4397 Cov.: 33 AF XY: 0.221 AC XY: 16430 AN XY: 74354

African (AFR) AF: 0.0792 AC: 3291 AN: 41540

American (AMR) AF: 0.195 AC: 2987 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 752 AN: 3470

East Asian (EAS) AF: 0.188 AC: 971 AN: 5178

South Asian (SAS) AF: 0.238 AC: 1150 AN: 4824

European-Finnish (FIN) AF: 0.337 AC: 3553 AN: 10536

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19785 AN: 67962

Other (OTH) AF: 0.216 AC: 455 AN: 2110

Alfa AF: 0.255 Hom.: 6948

Bravo AF: 0.200

Asia WGS AF: 0.163 AC: 566 AN: 3462

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	16
DANN	Benign	0.62
PhyloP100		0.14
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10520873;

hg19: chr5-7901230;