rs574132670

Variant names:

• chr1-11800250-C-T
• rs574132670
• NM_005957.5:c.548G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PP3_Moderate PP5_Very_Strong

The NM_005957.5(MTHFR):​c.548G>A​(p.Arg183Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000944878: Experimental studies have shown that this missense change affects MTHFR function (PMID:27743313)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.26
• Publications: 11 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000944878: Experimental studies have shown that this missense change affects MTHFR function (PMID: 27743313).; SCV001435288: Functional studies showed that the observed missense caused deleterious loss of MTHFR protein expression and activity (Burda et al. 2017).; SCV001825636: Published functional studies demonstrate a damaging effect (residual enzyme activity in fibroblasts ranging from 20-22%) (Burda et al., 2015); SCV005400899: Functional studies showed that the variant caused deleterious loss of MTHFR protein expression and activity (Burda et al., 2017).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_005957.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 1-11800250-C-T is Pathogenic according to our data. Variant chr1-11800250-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 187876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.548G>A	p.Arg183Gln	missense	Exon 4 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.671G>A	p.Arg224Gln	missense	Exon 4 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.668G>A	p.Arg223Gln	missense	Exon 4 of 12	NP_001397679.1	Q5SNW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.548G>A	p.Arg183Gln	missense	Exon 4 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.668G>A	p.Arg223Gln	missense	Exon 4 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.548G>A	p.Arg183Gln	missense	Exon 4 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000596 AC: 15 AN: 251492 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41 AN XY: 727242

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

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000383 AC: 33 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: 0.0000207 AC: 23 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152298 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (4)
2	-	-	not provided (2)
1	-	-	Neural tube defects, folate-sensitive (1)
1	-	-	Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.83		Loss of ubiquitination at K180 (P = 0.0613)
MVP		1.0
MPC		0.99
ClinPred		0.81	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.89
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -2

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

Other links and lift over

dbSNP: rs574132670; hg19: chr1-11860307; COSMIC: COSV64701602; COSMIC: COSV64701602;