1-11800401-C-T

Variant names:

• chr1-11800401-C-T
• rs2066471
• NM_005957.5:c.476-79G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):​c.476-79G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,064,840 control chromosomes in the GnomAD database, including 14,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1443 hom., cov: 32)
  • Exomes 𝑓: 0.16 (12706 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.240
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-11800401-C-T is Benign according to our data. Variant chr1-11800401-C-T is described in ClinVar as Benign. ClinVar VariationId is 1180162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.476-79G>A		intron_variant	Intron 3 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.476-79G>A		intron_variant	Intron 3 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18645 AN: 152036 Hom.: 1446 Cov.: 32

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.0977

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.160 AC: 145982 AN: 912686 Hom.: 12706 Cov.: 13 AF XY: 0.164 AC XY: 78460 AN XY: 477256

African (AFR) AF: 0.0269 AC: 612 AN: 22774

American (AMR) AF: 0.0808 AC: 3509 AN: 43402

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 4539 AN: 22566

East Asian (EAS) AF: 0.0945 AC: 3500 AN: 37050

South Asian (SAS) AF: 0.227 AC: 17061 AN: 75058

European-Finnish (FIN) AF: 0.169 AC: 8686 AN: 51534

Middle Eastern (MID) AF: 0.213 AC: 992 AN: 4664

European-Non Finnish (NFE) AF: 0.164 AC: 100531 AN: 613366

Other (OTH) AF: 0.155 AC: 6552 AN: 42272

GnomAD4 genome AF: 0.122 AC: 18638 AN: 152154 Hom.: 1443 Cov.: 32 AF XY: 0.123 AC XY: 9145 AN XY: 74386

African (AFR) AF: 0.0302 AC: 1256 AN: 41526

American (AMR) AF: 0.102 AC: 1560 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 705 AN: 3472

East Asian (EAS) AF: 0.0977 AC: 507 AN: 5188

South Asian (SAS) AF: 0.205 AC: 989 AN: 4814

European-Finnish (FIN) AF: 0.169 AC: 1785 AN: 10580

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11283 AN: 67978

Other (OTH) AF: 0.145 AC: 305 AN: 2110

Alfa AF: 0.123 Hom.: 791

Bravo AF: 0.113

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.7
DANN	Benign	0.68
PhyloP100		0.24
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: rs2066471; hg19: chr1-11860458; COSMIC: COSV64701666; COSMIC: COSV64701666;