NM_005957.5:c.1753-48C>G

Variant names:

• chr1-11790946-G-C
• rs3818762
• NM_005957.5:c.1753-48C>G

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.1753-48C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,559,624 control chromosomes in the GnomAD database, including 57,460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4601 hom., cov: 33)
  • Exomes 𝑓: 0.27 (52859 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.26
• Publications: 37 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=-1.04).
• BP6: Variant 1-11790946-G-C is Benign according to our data. Variant chr1-11790946-G-C is described in ClinVar as Benign. ClinVar VariationId is 1224887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.1753-48C>G		intron_variant	Intron 11 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1753-48C>G		intron_variant	Intron 11 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35715 AN: 151956 Hom.: 4602 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.260 AC: 63273 AN: 243380 AF XY: 0.272

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.215

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.274 AC: 385438 AN: 1407550 Hom.: 52859 Cov.: 25 AF XY: 0.279 AC XY: 196127 AN XY: 702690

African (AFR) AF: 0.135 AC: 4373 AN: 32404

American (AMR) AF: 0.147 AC: 6523 AN: 44280

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6743 AN: 25778

East Asian (EAS) AF: 0.208 AC: 8154 AN: 39280

South Asian (SAS) AF: 0.420 AC: 35646 AN: 84812

European-Finnish (FIN) AF: 0.283 AC: 14971 AN: 52884

Middle Eastern (MID) AF: 0.270 AC: 1459 AN: 5394

European-Non Finnish (NFE) AF: 0.274 AC: 291615 AN: 1064134

Other (OTH) AF: 0.272 AC: 15954 AN: 58584

GnomAD4 genome AF: 0.235 AC: 35737 AN: 152074 Hom.: 4601 Cov.: 33 AF XY: 0.237 AC XY: 17596 AN XY: 74330

African (AFR) AF: 0.148 AC: 6134 AN: 41506

American (AMR) AF: 0.173 AC: 2643 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 911 AN: 3468

East Asian (EAS) AF: 0.223 AC: 1150 AN: 5158

South Asian (SAS) AF: 0.417 AC: 2009 AN: 4814

European-Finnish (FIN) AF: 0.299 AC: 3163 AN: 10582

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18904 AN: 67954

Other (OTH) AF: 0.238 AC: 503 AN: 2110

Alfa AF: 0.257 Hom.: 955

Bravo AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:1

Aug 28, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.010
DANN	Benign	0.58
PhyloP100		-2.3
Mutation Taster		=19/81	disease causing (long InDel)

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: rs3818762; hg19: chr1-11851003; COSMIC: COSV100453746; COSMIC: COSV100453746;