1-11792243-C-T

Variant names:

• chr1-11792243-C-T
• rs1476413
• NM_005957.5:c.1632+35G>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.1632+35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,525,618 control chromosomes in the GnomAD database, including 56,824 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4505 hom., cov: 33)
  • Exomes 𝑓: 0.27 (52319 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.12
• Publications: 108 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-11792243-C-T is Benign according to our data. Variant chr1-11792243-C-T is described in ClinVar as Benign. ClinVar VariationId is 1170841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.398 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.1632+35G>A		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.1755+35G>A		intron	N/A	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.1752+35G>A		intron	N/A	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.1632+35G>A		intron	N/A	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.1752+35G>A		intron	N/A	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.1632+35G>A		intron	N/A	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35644 AN: 152054 Hom.: 4505 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.261 AC: 65718 AN: 251452 AF XY: 0.274

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.270 AC: 370338 AN: 1373446 Hom.: 52319 Cov.: 22 AF XY: 0.275 AC XY: 189376 AN XY: 688436

African (AFR) AF: 0.150 AC: 4765 AN: 31756

American (AMR) AF: 0.145 AC: 6466 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6276 AN: 25558

East Asian (EAS) AF: 0.208 AC: 8177 AN: 39274

South Asian (SAS) AF: 0.421 AC: 35542 AN: 84474

European-Finnish (FIN) AF: 0.284 AC: 15174 AN: 53378

Middle Eastern (MID) AF: 0.270 AC: 1513 AN: 5606

European-Non Finnish (NFE) AF: 0.269 AC: 276935 AN: 1031334

Other (OTH) AF: 0.270 AC: 15490 AN: 57432

GnomAD4 genome AF: 0.234 AC: 35669 AN: 152172 Hom.: 4505 Cov.: 33 AF XY: 0.236 AC XY: 17566 AN XY: 74396

African (AFR) AF: 0.161 AC: 6680 AN: 41538

American (AMR) AF: 0.173 AC: 2644 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 853 AN: 3466

East Asian (EAS) AF: 0.231 AC: 1195 AN: 5166

South Asian (SAS) AF: 0.414 AC: 1990 AN: 4812

European-Finnish (FIN) AF: 0.298 AC: 3150 AN: 10584

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18352 AN: 67984

Other (OTH) AF: 0.235 AC: 497 AN: 2112

Alfa AF: 0.259 Hom.: 23109

Bravo AF: 0.217

Asia WGS AF: 0.305 AC: 1062 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.7
DANN	Benign	0.80
PhyloP100		-1.1
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: rs1476413; hg19: chr1-11852300; COSMIC: COSV57171175; COSMIC: COSV57171175;