rs2066470

Variant names:

• chr1-11803000-G-A
• rs2066470
• NM_005957.5:c.117C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11803000-G-A
• chr1-11803000-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005957.5(MTHFR):​c.117C>T​(p.Pro39Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,948 control chromosomes in the GnomAD database, including 8,874 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (708 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8166 hom.)
• Consequence: MTHFR NM_005957.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -7.56
• Publications: 61 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-11803000-G-A is Benign according to our data. Variant chr1-11803000-G-A is described in ClinVar as Benign. ClinVar VariationId is 292246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

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.117C>T	p.Pro39Pro	synonymous	Exon 2 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.240C>T	p.Pro80Pro	synonymous	Exon 2 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.237C>T	p.Pro79Pro	synonymous	Exon 2 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.117C>T	p.Pro39Pro	synonymous	Exon 2 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.237C>T	p.Pro79Pro	synonymous	Exon 2 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.117C>T	p.Pro39Pro	synonymous	Exon 2 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.0930 AC: 14147 AN: 152076 Hom.: 711 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0650

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0766

GnomAD2 exomes AF: 0.0976 AC: 24504 AN: 251096 AF XY: 0.0997

Gnomad AFR exome AF: 0.0752

Gnomad AMR exome AF: 0.0622

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.0977

Gnomad OTH exome AF: 0.0869

GnomAD4 exome AF: 0.103 AC: 151010 AN: 1461754 Hom.: 8166 Cov.: 32 AF XY: 0.104 AC XY: 75660 AN XY: 727160

African (AFR) AF: 0.0781 AC: 2616 AN: 33480

American (AMR) AF: 0.0623 AC: 2785 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 896 AN: 26128

East Asian (EAS) AF: 0.109 AC: 4324 AN: 39700

South Asian (SAS) AF: 0.143 AC: 12322 AN: 86232

European-Finnish (FIN) AF: 0.112 AC: 5982 AN: 53410

Middle Eastern (MID) AF: 0.0432 AC: 249 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115567 AN: 1111928

Other (OTH) AF: 0.104 AC: 6269 AN: 60394

GnomAD4 genome AF: 0.0929 AC: 14144 AN: 152194 Hom.: 708 Cov.: 32 AF XY: 0.0944 AC XY: 7022 AN XY: 74398

African (AFR) AF: 0.0777 AC: 3228 AN: 41528

American (AMR) AF: 0.0646 AC: 988 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3472

East Asian (EAS) AF: 0.124 AC: 641 AN: 5174

South Asian (SAS) AF: 0.156 AC: 753 AN: 4818

European-Finnish (FIN) AF: 0.126 AC: 1338 AN: 10586

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6866 AN: 68012

Other (OTH) AF: 0.0768 AC: 162 AN: 2110

Alfa AF: 0.0931 Hom.: 1382

Bravo AF: 0.0859

Asia WGS AF: 0.127 AC: 440 AN: 3478

EpiCase AF: 0.0915

EpiControl AF: 0.0854

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.20
DANN	Benign	0.90
PhyloP100		-7.6
PromoterAI		0.0018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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: rs2066470; hg19: chr1-11863057; COSMIC: COSV56738175; COSMIC: COSV56738175;