NM_002454.3:c.1057+137T>C

Variant names:

• chr5-7885991-T-C
• rs162037
• NM_002454.3:c.1057+137T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002454.3(MTRR):​c.1057+137T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 1,115,726 control chromosomes in the GnomAD database, including 380,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.84 (53958 hom., cov: 32)
  • Exomes 𝑓: 0.82 (326678 hom.)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.771
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-7885991-T-C is Benign according to our data. Variant chr5-7885991-T-C is described in ClinVar as Benign. ClinVar VariationId is 1286746.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002454.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	NM_002454.3	MANE Select	c.1057+137T>C		intron	N/A	NP_002445.2
	MTRR	NM_001364440.2		c.1057+137T>C		intron	N/A	NP_001351369.1
	MTRR	NM_001364441.2		c.1057+137T>C		intron	N/A	NP_001351370.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	ENST00000440940.7	TSL:1 MANE Select	c.1057+137T>C		intron	N/A	ENSP00000402510.2
	MTRR	ENST00000264668.6	TSL:1	c.1138+137T>C		intron	N/A	ENSP00000264668.2
	MTRR	ENST00000513439.5	TSL:1	n.*764+137T>C		intron	N/A	ENSP00000426710.1

Frequencies

GnomAD3 genomes AF: 0.840 AC: 127784 AN: 152052 Hom.: 53906 Cov.: 32

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.805

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.826

GnomAD4 exome AF: 0.822 AC: 792137 AN: 963554 Hom.: 326678 AF XY: 0.820 AC XY: 408832 AN XY: 498642

African (AFR) AF: 0.890 AC: 20442 AN: 22972

American (AMR) AF: 0.832 AC: 33915 AN: 40748

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 17686 AN: 22794

East Asian (EAS) AF: 0.668 AC: 24475 AN: 36656

South Asian (SAS) AF: 0.800 AC: 59688 AN: 74584

European-Finnish (FIN) AF: 0.817 AC: 40170 AN: 49160

Middle Eastern (MID) AF: 0.778 AC: 2855 AN: 3672

European-Non Finnish (NFE) AF: 0.832 AC: 556847 AN: 669034

Other (OTH) AF: 0.821 AC: 36059 AN: 43934

GnomAD4 genome AF: 0.841 AC: 127902 AN: 152172 Hom.: 53958 Cov.: 32 AF XY: 0.839 AC XY: 62366 AN XY: 74368

African (AFR) AF: 0.890 AC: 36941 AN: 41526

American (AMR) AF: 0.848 AC: 12965 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2730 AN: 3472

East Asian (EAS) AF: 0.698 AC: 3605 AN: 5164

South Asian (SAS) AF: 0.805 AC: 3879 AN: 4818

European-Finnish (FIN) AF: 0.818 AC: 8656 AN: 10584

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56374 AN: 68006

Other (OTH) AF: 0.825 AC: 1740 AN: 2110

Alfa AF: 0.833 Hom.: 7981

Bravo AF: 0.842

Asia WGS AF: 0.747 AC: 2600 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.72
DANN	Benign	0.43
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs162037; hg19: chr5-7886104;