1-11790692-C-T

Variant names:

• chr1-11790692-C-T
• rs45572531
• NM_005957.5:c.1959G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005957.5(MTHFR):​c.1959G>A​(p.Thr653Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,614,138 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: MTHFR NM_005957.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.67
• Publications: 2 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 (MetaRNN=0.0048999786).
• BP6: Variant 1-11790692-C-T is Benign according to our data. Variant chr1-11790692-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 498489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00186 (283/152280) while in subpopulation AFR AF = 0.00657 (273/41550). AF 95% confidence interval is 0.00593. There are 4 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1959G>A	p.Thr653Thr	synonymous	Exon 12 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.2082G>A	p.Thr694Thr	synonymous	Exon 12 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.2079G>A	p.Thr693Thr	synonymous	Exon 12 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.1959G>A	p.Thr653Thr	synonymous	Exon 12 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.2079G>A	p.Thr693Thr	synonymous	Exon 12 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.1959G>A	p.Thr653Thr	synonymous	Exon 12 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152162 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000474 AC: 119 AN: 251294 AF XY: 0.000361

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000244 AC: 356 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 162 AN XY: 727220

African (AFR) AF: 0.00759 AC: 254 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111996

Other (OTH) AF: 0.000629 AC: 38 AN: 60396

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152280 Hom.: 4 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74462

African (AFR) AF: 0.00657 AC: 273 AN: 41550

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000698 Hom.: 0

Bravo AF: 0.00199

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000576 AC: 70

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Schizophrenia;C1856061:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.024
DANN	Benign	0.61
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0049	T
PhyloP100		-4.7
GERP RS		-10
Mutation Taster		=100/0	polymorphism

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: rs45572531; hg19: chr1-11850749; COSMIC: COSV100453372; COSMIC: COSV100453372;