NM_002454.3:c.1761T>C

Variant names:

• chr5-7896948-T-C
• rs6874544
• NM_002454.3:c.1761T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002454.3(MTRR):​c.1761T>C​(p.Tyr587Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,614,002 control chromosomes in the GnomAD database, including 364 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: 32)
  • Exomes 𝑓: 0.020 (331 hom.)
• Consequence: MTRR NM_002454.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.132
• Publications: 7 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=-0.81).
• BP6: Variant 5-7896948-T-C is Benign according to our data. Variant chr5-7896948-T-C is described in ClinVar as Benign. ClinVar VariationId is 138299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2508/152328) while in subpopulation NFE AF = 0.0252 (1715/68034). AF 95% confidence interval is 0.0242. There are 33 homozygotes in GnomAd4. There are 1193 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.1761T>C	p.Tyr587Tyr	synonymous	Exon 13 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1761T>C	p.Tyr587Tyr	synonymous	Exon 13 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1761T>C	p.Tyr587Tyr	synonymous	Exon 13 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.1761T>C	p.Tyr587Tyr	synonymous	Exon 13 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.1842T>C	p.Tyr614Tyr	synonymous	Exon 13 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*1468T>C		non_coding_transcript_exon	Exon 13 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2507 AN: 152210 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00731

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0154 AC: 3859 AN: 251024 AF XY: 0.0150

Gnomad AFR exome AF: 0.00774

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0203 AC: 29617 AN: 1461674 Hom.: 331 Cov.: 33 AF XY: 0.0198 AC XY: 14393 AN XY: 727158

African (AFR) AF: 0.00672 AC: 225 AN: 33476

American (AMR) AF: 0.0157 AC: 702 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 292 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39682

South Asian (SAS) AF: 0.00261 AC: 225 AN: 86252

European-Finnish (FIN) AF: 0.0125 AC: 670 AN: 53416

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.0237 AC: 26356 AN: 1111836

Other (OTH) AF: 0.0186 AC: 1123 AN: 60386

GnomAD4 genome AF: 0.0165 AC: 2508 AN: 152328 Hom.: 33 Cov.: 32 AF XY: 0.0160 AC XY: 1193 AN XY: 74488

African (AFR) AF: 0.00731 AC: 304 AN: 41568

American (AMR) AF: 0.0141 AC: 216 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0252 AC: 1715 AN: 68034

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

Alfa AF: 0.0217 Hom.: 138

Bravo AF: 0.0166

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0182

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Methylcobalamin deficiency type cblE (3)
-	-	2	not provided (2)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.0
DANN	Benign	0.87
PhyloP100		-0.13
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: rs6874544; hg19: chr5-7897061;