chr5-7893695-C-G

Variant names:

• chr5-7893695-C-G
• rs17267737
• NM_002454.3:c.1557+782C>G

Variant summary

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

The NM_002454.3(MTRR):​c.1557+782C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,170 control chromosomes in the GnomAD database, including 1,873 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 0.14 (1872 hom., cov: 32)
  • Exomes 𝑓: 0.11 (1 hom.)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.605
• Publications: 2 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, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	NM_002454.3	MANE Select	c.1557+782C>G		intron	N/A	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1557+782C>G		intron	N/A	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1557+782C>G		intron	N/A	NP_001351370.1	Q9UBK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	ENST00000440940.7	TSL:1 MANE Select	c.1557+782C>G		intron	N/A	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.1638+782C>G		intron	N/A	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*1264+782C>G		intron	N/A	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20621 AN: 152008 Hom.: 1872 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0869

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.114 AC: 5 AN: 44 Hom.: 1 Cov.: 0 AF XY: 0.0833 AC XY: 2 AN XY: 24

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

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) AF: 0.119 AC: 5 AN: 42

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.136 AC: 20625 AN: 152126 Hom.: 1872 Cov.: 32 AF XY: 0.133 AC XY: 9921 AN XY: 74370

African (AFR) AF: 0.0374 AC: 1554 AN: 41528

American (AMR) AF: 0.104 AC: 1588 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 640 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5174

South Asian (SAS) AF: 0.0876 AC: 422 AN: 4816

European-Finnish (FIN) AF: 0.194 AC: 2053 AN: 10578

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13867 AN: 67974

Other (OTH) AF: 0.111 AC: 235 AN: 2114

Alfa AF: 0.167 Hom.: 294

Bravo AF: 0.124

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.65
PhyloP100		0.60
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: rs17267737; hg19: chr5-7893808;