rs543016186

Variant names:

• chr1-11795125-C-A
• rs543016186
• NM_005957.5:c.1004G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11795125-C-A
• chr1-11795125-C-G
• chr1-11795125-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_005957.5(MTHFR):​c.1004G>T​(p.Arg335Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,730 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R335C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11795126-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2054912.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.1004G>T	p.Arg335Leu	missense	Exon 6 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1127G>T	p.Arg376Leu	missense	Exon 6 of 12	NP_001317287.1
	MTHFR	NM_001410750.1		c.1124G>T	p.Arg375Leu	missense	Exon 6 of 12	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1004G>T	p.Arg335Leu	missense	Exon 6 of 12	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.1124G>T	p.Arg375Leu	missense	Exon 6 of 12	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.1004G>T	p.Arg335Leu	missense	Exon 6 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460730 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726766

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52290

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	-0.0058
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.4	L
PhyloP100		3.6
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Benign	0.29	T
Sift4G	Benign	0.23	T
Polyphen		0.20	B
Vest4		0.59
MutPred		0.68		Gain of catalytic residue at R335 (P = 0.0134)
MVP		0.94
MPC		0.47
ClinPred		0.97	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.73
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs543016186; hg19: chr1-11855182; COSMIC: COSV64877245; COSMIC: COSV64877245;