1-11800786-G-A

Variant names:

• chr1-11800786-G-A
• rs17037390
• NM_005957.5:c.475+375C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005957.5(MTHFR):​c.475+375C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 395,534 control chromosomes in the GnomAD database, including 5,572 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2454 hom., cov: 32)
  • Exomes 𝑓: 0.16 (3118 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246
• Publications: 30 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.475+375C>T		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.598+375C>T		intron	N/A	NP_001317287.1
	MTHFR	NM_001410750.1		c.595+375C>T		intron	N/A	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.475+375C>T		intron	N/A	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.595+375C>T		intron	N/A	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.475+375C>T		intron	N/A	ENSP00000365777.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26326 AN: 151988 Hom.: 2450 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0942

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.156 AC: 37930 AN: 243428 Hom.: 3118 Cov.: 0 AF XY: 0.158 AC XY: 20652 AN XY: 131106

African (AFR) AF: 0.235 AC: 1673 AN: 7126

American (AMR) AF: 0.112 AC: 1281 AN: 11418

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 650 AN: 6428

East Asian (EAS) AF: 0.118 AC: 1353 AN: 11514

South Asian (SAS) AF: 0.181 AC: 7335 AN: 40618

European-Finnish (FIN) AF: 0.145 AC: 1764 AN: 12144

Middle Eastern (MID) AF: 0.151 AC: 140 AN: 926

European-Non Finnish (NFE) AF: 0.155 AC: 21732 AN: 140522

Other (OTH) AF: 0.157 AC: 2002 AN: 12732

GnomAD4 genome AF: 0.173 AC: 26352 AN: 152106 Hom.: 2454 Cov.: 32 AF XY: 0.174 AC XY: 12910 AN XY: 74356

African (AFR) AF: 0.231 AC: 9586 AN: 41440

American (AMR) AF: 0.121 AC: 1854 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0942 AC: 327 AN: 3470

East Asian (EAS) AF: 0.125 AC: 649 AN: 5172

South Asian (SAS) AF: 0.200 AC: 963 AN: 4820

European-Finnish (FIN) AF: 0.162 AC: 1711 AN: 10588

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10821 AN: 68008

Other (OTH) AF: 0.154 AC: 326 AN: 2112

Alfa AF: 0.156 Hom.: 2719

Bravo AF: 0.171

Asia WGS AF: 0.170 AC: 590 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.8
DANN	Benign	0.79
PhyloP100		-0.25
Mutation Taster		=100/0	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: rs17037390; hg19: chr1-11860843;