rs9282788

Variant names:

• chr5-7900519-T-C
• rs9282788
• NM_002454.3:c.*461T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-7900519-T-C
• chr5-7900519-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002454.3(MTRR):​c.*461T>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 0.0163 in 169,972 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 33)
  • Exomes 𝑓: 0.015 (2 hom.)
• Consequence: MTRR NM_002454.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-7900519-T-C is Benign according to our data. Variant chr5-7900519-T-C is described in ClinVar as Benign. ClinVar VariationId is 904711.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2510/152358) while in subpopulation NFE AF = 0.0253 (1718/68030). AF 95% confidence interval is 0.0243. There are 33 homozygotes in GnomAd4. There are 1196 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

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.*461T>C		3_prime_UTR	Exon 15 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.*461T>C		3_prime_UTR	Exon 15 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.*461T>C		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.*461T>C		3_prime_UTR	Exon 15 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.*461T>C		3_prime_UTR	Exon 15 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000869929.1		c.*461T>C		3_prime_UTR	Exon 15 of 15	ENSP00000539988.1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2509 AN: 152240 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00730

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0149 AC: 262 AN: 17614 Hom.: 2 Cov.: 0 AF XY: 0.0146 AC XY: 135 AN XY: 9232

African (AFR) AF: 0.00575 AC: 1 AN: 174

American (AMR) AF: 0.0153 AC: 45 AN: 2944

Ashkenazi Jewish (ASJ) AF: 0.00855 AC: 2 AN: 234

East Asian (EAS) AF: 0.00 AC: 0 AN: 1294

South Asian (SAS) AF: 0.000829 AC: 2 AN: 2412

European-Finnish (FIN) AF: 0.00763 AC: 6 AN: 786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.0214 AC: 193 AN: 9036

Other (OTH) AF: 0.0183 AC: 13 AN: 712

GnomAD4 genome AF: 0.0165 AC: 2510 AN: 152358 Hom.: 33 Cov.: 33 AF XY: 0.0161 AC XY: 1196 AN XY: 74512

African (AFR) AF: 0.00731 AC: 304 AN: 41602

American (AMR) AF: 0.0141 AC: 216 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4822

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1718 AN: 68030

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0163 Hom.: 11

Bravo AF: 0.0167

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.3
DANN	Benign	0.56
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

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: rs9282788; hg19: chr5-7900632;