1-11794839-G-C

Variant names:

• chr1-11794839-G-C
• rs2066462
• NM_005957.5:c.1056C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005957.5(MTHFR):​c.1056C>G​(p.Ser352Arg) 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 1,461,400 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S352S) has been classified as Benign.

• 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: -0.561
• Publications: 0 publications found

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]

MTHFR Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. 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
	MTHFR	NM_005957.5	MANE Select	c.1056C>G	p.Ser352Arg	missense	Exon 7 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1179C>G	p.Ser393Arg	missense	Exon 7 of 12	NP_001317287.1
	MTHFR	NM_001410750.1		c.1176C>G	p.Ser392Arg	missense	Exon 7 of 12	NP_001397679.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1056C>G	p.Ser352Arg	missense	Exon 7 of 12	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.1176C>G	p.Ser392Arg	missense	Exon 7 of 12	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.1056C>G	p.Ser352Arg	missense	Exon 7 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461400 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726900

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111656

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-0.56
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.020	D
Polyphen		0.68	P
Vest4		0.81
MutPred		0.37		Gain of MoRF binding (P = 0.0105)
MVP		0.64
MPC		0.96
ClinPred		0.99	D
GERP RS		-5.1
Varity_R		0.89
gMVP		0.95
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: 0

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

Other links and lift over

dbSNP: rs2066462; hg19: chr1-11854896;