rs148909799

Variant names:

• chr5-7899943-A-G
• rs148909799
• NM_002454.3:c.1982A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-7899943-A-G
• chr5-7899943-A-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002454.3(MTRR):​c.1982A>G​(p.His661Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,614,224 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H661H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.67
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00992918).
• BP6: Variant 5-7899943-A-G is Benign according to our data. Variant chr5-7899943-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203841.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00192 (293/152360) while in subpopulation NFE AF = 0.00345 (235/68032). AF 95% confidence interval is 0.00309. There are 1 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.1982A>G	p.His661Arg	missense	Exon 15 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1982A>G	p.His661Arg	missense	Exon 15 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1982A>G	p.His661Arg	missense	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.1982A>G	p.His661Arg	missense	Exon 15 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.2063A>G	p.His688Arg	missense	Exon 15 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*1689A>G		non_coding_transcript_exon	Exon 15 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 293 AN: 152242 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000723

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00187 AC: 471 AN: 251296 AF XY: 0.00194

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00323 AC: 4719 AN: 1461864 Hom.: 9 Cov.: 31 AF XY: 0.00320 AC XY: 2330 AN XY: 727232

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00228 AC: 197 AN: 86258

European-Finnish (FIN) AF: 0.000899 AC: 48 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00385 AC: 4280 AN: 1112000

Other (OTH) AF: 0.00215 AC: 130 AN: 60396

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152360 Hom.: 1 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74506

African (AFR) AF: 0.000721 AC: 30 AN: 41594

American (AMR) AF: 0.000457 AC: 7 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00345 AC: 235 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00264 Hom.: 5

Bravo AF: 0.00186

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	-	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	Methylcobalamin deficiency type cblE (1)
-	-	1	MTRR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.88
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.18	N
PhyloP100		2.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.19
Sift	Benign	0.97	T
Sift4G	Benign	0.52	T
Vest4		0.13
MVP		0.70
MPC		0.064
ClinPred		0.018	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.44
Mutation Taster		=90/10	polymorphism

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: rs148909799; hg19: chr5-7900056; COSMIC: COSV99241642; COSMIC: COSV99241642;