rs9332

Variant names:

• chr5-7900599-G-A
• rs9332
• NM_002454.3:c.*541G>A

Variant summary

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

The NM_002454.3(MTRR):​c.*541G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,788 control chromosomes in the GnomAD database, including 4,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4511 hom., cov: 33)
  • Exomes 𝑓: 0.073 (3 hom.)
• Consequence: MTRR NM_002454.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.157
• Publications: 22 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=-0.77).
• BP6: Variant 5-7900599-G-A is Benign according to our data. Variant chr5-7900599-G-A is described in ClinVar as Benign. ClinVar VariationId is 354370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 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.*541G>A		3_prime_UTR	Exon 15 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.*541G>A		3_prime_UTR	Exon 15 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.*541G>A		3_prime_UTR	Exon 15 of 15	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.*541G>A		3_prime_UTR	Exon 15 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.*541G>A		3_prime_UTR	Exon 15 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000869929.1		c.*541G>A		3_prime_UTR	Exon 15 of 15	ENSP00000539988.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31185 AN: 151906 Hom.: 4496 Cov.: 33

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.0733 AC: 56 AN: 764 Hom.: 3 Cov.: 0 AF XY: 0.0783 AC XY: 34 AN XY: 434

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.143 AC: 6 AN: 42

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.143 AC: 2 AN: 14

European-Finnish (FIN) AF: 0.0516 AC: 22 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0871 AC: 23 AN: 264

Other (OTH) AF: 0.167 AC: 2 AN: 12

GnomAD4 genome AF: 0.206 AC: 31251 AN: 152024 Hom.: 4511 Cov.: 33 AF XY: 0.203 AC XY: 15107 AN XY: 74290

African (AFR) AF: 0.381 AC: 15807 AN: 41474

American (AMR) AF: 0.296 AC: 4517 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 606 AN: 3470

East Asian (EAS) AF: 0.147 AC: 759 AN: 5162

South Asian (SAS) AF: 0.141 AC: 680 AN: 4808

European-Finnish (FIN) AF: 0.0690 AC: 728 AN: 10556

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7643 AN: 67976

Other (OTH) AF: 0.200 AC: 422 AN: 2114

Alfa AF: 0.147 Hom.: 2096

Bravo AF: 0.232

Asia WGS AF: 0.152 AC: 529 AN: 3474

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	-0.77
CADD	Benign	4.0
DANN	Benign	0.71
PhyloP100		0.16
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: rs9332; hg19: chr5-7900712; COSMIC: COSV105099451; COSMIC: COSV105099451;