NM_002454.3:c.524C>T

Variant names:

• chr5-7878066-C-T
• rs1532268
• NM_002454.3:c.524C>T

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.524C>T​(p.Ser175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,402 control chromosomes in the GnomAD database, including 100,433 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S175P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (7888 hom., cov: 30)
  • Exomes 𝑓: 0.35 (92545 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: -2.35
• Publications: 133 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=0.0014089942).
• BP6: Variant 5-7878066-C-T is Benign according to our data. Variant chr5-7878066-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 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.524C>T	p.Ser175Leu	missense	Exon 5 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.524C>T	p.Ser175Leu	missense	Exon 5 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.524C>T	p.Ser175Leu	missense	Exon 5 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.524C>T	p.Ser175Leu	missense	Exon 5 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.605C>T	p.Ser202Leu	missense	Exon 5 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*231C>T		non_coding_transcript_exon	Exon 5 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47805 AN: 151460 Hom.: 7871 Cov.: 30

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.315

GnomAD2 exomes AF: 0.311 AC: 78080 AN: 251244 AF XY: 0.320

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.364

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.351 AC: 512993 AN: 1461824 Hom.: 92545 Cov.: 61 AF XY: 0.353 AC XY: 256369 AN XY: 727202

African (AFR) AF: 0.269 AC: 9002 AN: 33480

American (AMR) AF: 0.176 AC: 7851 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9493 AN: 26132

East Asian (EAS) AF: 0.123 AC: 4886 AN: 39700

South Asian (SAS) AF: 0.364 AC: 31403 AN: 86258

European-Finnish (FIN) AF: 0.323 AC: 17276 AN: 53410

Middle Eastern (MID) AF: 0.398 AC: 2292 AN: 5766

European-Non Finnish (NFE) AF: 0.369 AC: 409778 AN: 1111964

Other (OTH) AF: 0.348 AC: 21012 AN: 60396

GnomAD4 genome AF: 0.316 AC: 47854 AN: 151578 Hom.: 7888 Cov.: 30 AF XY: 0.313 AC XY: 23148 AN XY: 74012

African (AFR) AF: 0.265 AC: 10970 AN: 41342

American (AMR) AF: 0.240 AC: 3659 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1278 AN: 3460

East Asian (EAS) AF: 0.150 AC: 767 AN: 5114

South Asian (SAS) AF: 0.377 AC: 1799 AN: 4776

European-Finnish (FIN) AF: 0.328 AC: 3428 AN: 10448

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.366 AC: 24822 AN: 67876

Other (OTH) AF: 0.317 AC: 666 AN: 2102

Alfa AF: 0.347 Hom.: 40447

Bravo AF: 0.304

TwinsUK AF: 0.373 AC: 1384

ALSPAC AF: 0.365 AC: 1407

ESP6500AA AF: 0.266 AC: 1172

ESP6500EA AF: 0.360 AC: 3097

ExAC AF: 0.315 AC: 38271

Asia WGS AF: 0.293 AC: 1017 AN: 3478

EpiCase AF: 0.366

EpiControl AF: 0.369

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Methylcobalamin deficiency type cblE (4)
-	-	4	not specified (4)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	1	-	Gastrointestinal stromal tumor (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0060
DANN	Benign	0.69
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-2.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.022
Sift	Benign	0.33	T
Sift4G	Benign	0.40	T
Vest4		0.026
MPC		0.043
ClinPred		0.019	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.24
Mutation Taster		=97/3	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: rs1532268; hg19: chr5-7878179; COSMIC: COSV52941765; COSMIC: COSV52941765;