5-7899943-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002454.3(MTRR):​c.1982A>C​(p.His661Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H661R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34691268).

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>C	p.His661Pro	missense	Exon 15 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1982A>C	p.His661Pro	missense	Exon 15 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1982A>C	p.His661Pro	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>C	p.His661Pro	missense	Exon 15 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.2063A>C	p.His688Pro	missense	Exon 15 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*1689A>C		non_coding_transcript_exon	Exon 15 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Benign	0.92
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.080	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.7
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Benign	0.12	T
Sift4G	Benign	0.25	T
Vest4		0.31
MutPred		0.67		Loss of catalytic residue at D689 (P = 0.1129)
MVP		0.85
MPC		0.12
ClinPred		0.61	D
GERP RS		3.3
Varity_R		0.71
gMVP		0.74
Mutation Taster		=85/15	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: rs148909799; hg19: chr5-7900056;