chr1-11794441-C-G

Position:

• chr1-11794441-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005957.5(MTHFR):​c.1264G>C​(p.Gly422Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin Lovd.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.39

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.1264G>C	p.Gly422Arg	missense_variant	8/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1264G>C	p.Gly422Arg	missense_variant	8/12	1	NM_005957.5	ENSP00000365775	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251464 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;D;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.0	H;.;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.2	D;D;D;D;.;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0050	D;D;D;D;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;.;.;.
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		0.73
MutPred		0.27		Gain of solvent accessibility (P = 0.0055);.;.;Gain of solvent accessibility (P = 0.0055);.;Gain of solvent accessibility (P = 0.0055);.;
MVP		0.91
MPC		1.0
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.77
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45571736; hg19: chr1-11854498;