rs326119

Variant names:

• chr5-7869970-C-A
• rs326119
• NM_002454.3:c.-26+755C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-7869970-C-A
• chr5-7869970-C-G
• chr5-7869970-C-T

Variant summary

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

The NM_001364440.2(MTRR):​c.-112C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 967,338 control chromosomes in the GnomAD database, including 130,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25058 hom., cov: 33)
  • Exomes 𝑓: 0.51 (105307 hom.)
• Consequence: MTRR NM_001364440.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.320
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-7869970-C-A is Benign according to our data. Variant chr5-7869970-C-A is described in ClinVar as Benign. ClinVar VariationId is 1166106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364440.2. 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.-26+755C>A		intron	N/A	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.-112C>A		5_prime_UTR	Exon 1 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.-26+252C>A		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.-26+755C>A		intron	N/A	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.56+781C>A		intron	N/A	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.-26+755C>A		intron	N/A	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86184 AN: 151910 Hom.: 25034 Cov.: 33

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.506 AC: 412728 AN: 815310 Hom.: 105307 AF XY: 0.506 AC XY: 190903 AN XY: 377150

African (AFR) AF: 0.679 AC: 10460 AN: 15412

American (AMR) AF: 0.684 AC: 654 AN: 956

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 2157 AN: 5070

East Asian (EAS) AF: 0.653 AC: 2316 AN: 3544

South Asian (SAS) AF: 0.624 AC: 10093 AN: 16162

European-Finnish (FIN) AF: 0.507 AC: 139 AN: 274

Middle Eastern (MID) AF: 0.453 AC: 720 AN: 1588

European-Non Finnish (NFE) AF: 0.499 AC: 372131 AN: 745566

Other (OTH) AF: 0.526 AC: 14058 AN: 26738

GnomAD4 genome AF: 0.567 AC: 86257 AN: 152028 Hom.: 25058 Cov.: 33 AF XY: 0.572 AC XY: 42460 AN XY: 74292

African (AFR) AF: 0.663 AC: 27486 AN: 41478

American (AMR) AF: 0.637 AC: 9739 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 1457 AN: 3464

East Asian (EAS) AF: 0.657 AC: 3387 AN: 5156

South Asian (SAS) AF: 0.639 AC: 3080 AN: 4820

European-Finnish (FIN) AF: 0.533 AC: 5624 AN: 10546

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.496 AC: 33733 AN: 67966

Other (OTH) AF: 0.550 AC: 1164 AN: 2116

Alfa AF: 0.525 Hom.: 5029

Bravo AF: 0.575

Asia WGS AF: 0.629 AC: 2189 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Methylcobalamin deficiency type cblE (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.45
PhyloP100		-0.32
PromoterAI		-0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs326119; hg19: chr5-7870083;