1-11786602-ATTTTTTTTT-AT

Variant names:

• chr1-11786602-ATTTTTTTT-A
• rs55780505
• NM_005957.5:c.*4070_*4077delAAAAAAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001330358.2(MTHFR):​c.*4070_*4077delAAAAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 142,226 control chromosomes in the GnomAD database, including 421 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (420 hom., cov: 0)
  • Exomes 𝑓: 0.50 (1 hom.)
• Consequence: MTHFR NM_001330358.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.308
• Publications: 3 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]

C1orf167 (HGNC:25262): (chromosome 1 open reading frame 167) Implicated in coronary artery disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330358.2. 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.*4070_*4077delAAAAAAAA		3_prime_UTR	Exon 12 of 12	NP_005948.3
	C1orf167	NM_001010881.2	MANE Select	c.3568-774_3568-767delTTTTTTTT		intron	N/A	NP_001010881.1
	MTHFR	NM_001330358.2		c.*4070_*4077delAAAAAAAA		3_prime_UTR	Exon 12 of 12	NP_001317287.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.*4070_*4077delAAAAAAAA		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3
	MTHFR	ENST00000376592.6	TSL:1	c.*4070_*4077delAAAAAAAA		3_prime_UTR	Exon 12 of 12	ENSP00000365777.1
	C1orf167	ENST00000688073.1	MANE Select	c.3568-774_3568-767delTTTTTTTT		intron	N/A	ENSP00000510540.1

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 10649 AN: 142188 Hom.: 419 Cov.: 0

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.0982

Gnomad AMR AF: 0.0610

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.000835

Gnomad SAS AF: 0.0889

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0824

Gnomad OTH AF: 0.0913

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 1 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 2 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0750 AC: 10661 AN: 142222 Hom.: 420 Cov.: 0 AF XY: 0.0740 AC XY: 5069 AN XY: 68454

African (AFR) AF: 0.0826 AC: 3194 AN: 38650

American (AMR) AF: 0.0609 AC: 873 AN: 14336

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 169 AN: 3370

East Asian (EAS) AF: 0.000838 AC: 4 AN: 4772

South Asian (SAS) AF: 0.0889 AC: 389 AN: 4378

European-Finnish (FIN) AF: 0.0415 AC: 333 AN: 8022

Middle Eastern (MID) AF: 0.117 AC: 32 AN: 274

European-Non Finnish (NFE) AF: 0.0824 AC: 5402 AN: 65568

Other (OTH) AF: 0.0905 AC: 178 AN: 1966

Alfa AF: 0.0668 Hom.: 551

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Neural tube defects, folate-sensitive (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55780505; hg19: chr1-11846659;