chr5-7885794-C-G

Variant names:

• chr5-7885794-C-G
• rs10064631
• NM_002454.3:c.997C>G

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.997C>G​(p.Leu333Val) variant causes a missense change. The variant allele was found at a frequency of 0.00767 in 1,613,870 control chromosomes in the GnomAD database, including 863 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L333F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (454 hom., cov: 31)
  • Exomes 𝑓: 0.0041 (409 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.24
• Publications: 16 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 (MetaRNN=0.0018704832).
• BP6: Variant 5-7885794-C-G is Benign according to our data. Variant chr5-7885794-C-G is described in ClinVar as Benign. ClinVar VariationId is 354359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 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.997C>G	p.Leu333Val	missense	Exon 7 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.997C>G	p.Leu333Val	missense	Exon 7 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.997C>G	p.Leu333Val	missense	Exon 7 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.997C>G	p.Leu333Val	missense	Exon 7 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.1078C>G	p.Leu360Val	missense	Exon 7 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*704C>G		non_coding_transcript_exon	Exon 7 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.0418 AC: 6355 AN: 151880 Hom.: 453 Cov.: 31

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0106 AC: 2655 AN: 251464 AF XY: 0.00765

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00412 AC: 6016 AN: 1461872 Hom.: 409 Cov.: 35 AF XY: 0.00347 AC XY: 2526 AN XY: 727242

African (AFR) AF: 0.151 AC: 5066 AN: 33478

American (AMR) AF: 0.00680 AC: 304 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.0000827 AC: 92 AN: 1111998

Other (OTH) AF: 0.00844 AC: 510 AN: 60396

GnomAD4 genome AF: 0.0419 AC: 6370 AN: 151998 Hom.: 454 Cov.: 31 AF XY: 0.0400 AC XY: 2973 AN XY: 74306

African (AFR) AF: 0.146 AC: 6061 AN: 41404

American (AMR) AF: 0.0140 AC: 214 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 67988

Other (OTH) AF: 0.0289 AC: 61 AN: 2108

Alfa AF: 0.00254 Hom.: 5

Bravo AF: 0.0481

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.145 AC: 639

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0133 AC: 1618

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.039	D
Vest4		0.23
MPC		0.32
ClinPred		0.0081	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.52
Mutation Taster		=66/34	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: rs10064631; hg19: chr5-7885907; COSMIC: COSV52944847; COSMIC: COSV52944847;