rs10380

Variant names:

• chr5-7897078-C-T
• rs10380
• NM_002454.3:c.1783C>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.1783C>T​(p.His595Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,374 control chromosomes in the GnomAD database, including 15,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. H595R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (3416 hom., cov: 32)
  • Exomes 𝑓: 0.11 (12338 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 0.559
• Publications: 87 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=0.012291789).
• BP6: Variant 5-7897078-C-T is Benign according to our data. Variant chr5-7897078-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 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.1783C>T	p.His595Tyr	missense	Exon 14 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1783C>T	p.His595Tyr	missense	Exon 14 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1783C>T	p.His595Tyr	missense	Exon 14 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.1783C>T	p.His595Tyr	missense	Exon 14 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.1864C>T	p.His622Tyr	missense	Exon 14 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*1490C>T		non_coding_transcript_exon	Exon 14 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27185 AN: 152012 Hom.: 3398 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0940

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.157 AC: 39347 AN: 250918 AF XY: 0.145

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.0699

Gnomad NFE exome AF: 0.0952

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.113 AC: 165838 AN: 1461244 Hom.: 12338 Cov.: 34 AF XY: 0.112 AC XY: 81709 AN XY: 726952

African (AFR) AF: 0.334 AC: 11177 AN: 33454

American (AMR) AF: 0.341 AC: 15257 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4061 AN: 26128

East Asian (EAS) AF: 0.140 AC: 5567 AN: 39690

South Asian (SAS) AF: 0.137 AC: 11829 AN: 86236

European-Finnish (FIN) AF: 0.0682 AC: 3641 AN: 53408

Middle Eastern (MID) AF: 0.142 AC: 818 AN: 5768

European-Non Finnish (NFE) AF: 0.0951 AC: 105727 AN: 1111504

Other (OTH) AF: 0.129 AC: 7761 AN: 60370

GnomAD4 genome AF: 0.179 AC: 27246 AN: 152130 Hom.: 3416 Cov.: 32 AF XY: 0.178 AC XY: 13263 AN XY: 74396

African (AFR) AF: 0.328 AC: 13603 AN: 41466

American (AMR) AF: 0.273 AC: 4170 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 537 AN: 3470

East Asian (EAS) AF: 0.147 AC: 762 AN: 5174

South Asian (SAS) AF: 0.136 AC: 653 AN: 4818

European-Finnish (FIN) AF: 0.0646 AC: 685 AN: 10606

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0940 AC: 6391 AN: 68004

Other (OTH) AF: 0.172 AC: 363 AN: 2112

Alfa AF: 0.126 Hom.: 7703

Bravo AF: 0.203

TwinsUK AF: 0.0952 AC: 353

ALSPAC AF: 0.0911 AC: 351

ESP6500AA AF: 0.320 AC: 1410

ESP6500EA AF: 0.0978 AC: 841

ExAC AF: 0.151 AC: 18324

Asia WGS AF: 0.145 AC: 505 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.102

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.47
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.56
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Vest4		0.065
MPC		0.052
ClinPred		0.0019	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.39
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs10380; hg19: chr5-7897191; COSMIC: COSV52944133; COSMIC: COSV52944133;