1-11786602-ATTTTTTTTT-ATTTTTTTTTT

Variant names:

• chr1-11786602-A-AT
• rs55780505
• NM_005957.5:c.*4077dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005957.5(MTHFR):​c.*4077dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00363 (516/142196) while in subpopulation AFR AF = 0.00908 (351/38648). AF 95% confidence interval is 0.0083. There are 5 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.*4077dupA		3_prime_UTR	Exon 12 of 12	NP_005948.3
	C1orf167	NM_001010881.2	MANE Select	c.3568-767dupT		intron	N/A	NP_001010881.1	Q5SNV9-1
	MTHFR	NM_001330358.2		c.*4077dupA		3_prime_UTR	Exon 12 of 12	NP_001317287.1	P42898-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.*4077dupA		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000376592.6	TSL:1	c.*4077dupA		3_prime_UTR	Exon 12 of 12	ENSP00000365777.1	P42898-1
	C1orf167	ENST00000688073.1	MANE Select	c.3568-767dupT		intron	N/A	ENSP00000510540.1	Q5SNV9-1

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 516 AN: 142166 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.0226

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000297

Gnomad EAS AF: 0.00125

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00175

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.00111

Gnomad OTH AF: 0.00410

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 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: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00363 AC: 516 AN: 142196 Hom.: 5 Cov.: 0 AF XY: 0.00352 AC XY: 241 AN XY: 68434

African (AFR) AF: 0.00908 AC: 351 AN: 38648

American (AMR) AF: 0.00209 AC: 30 AN: 14332

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 1 AN: 3370

East Asian (EAS) AF: 0.00126 AC: 6 AN: 4772

South Asian (SAS) AF: 0.00229 AC: 10 AN: 4376

European-Finnish (FIN) AF: 0.00175 AC: 14 AN: 8018

Middle Eastern (MID) AF: 0.0109 AC: 3 AN: 274

European-Non Finnish (NFE) AF: 0.00111 AC: 73 AN: 65552

Other (OTH) AF: 0.00407 AC: 8 AN: 1968

Alfa AF: 0.00 Hom.: 551

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs55780505; hg19: chr1-11846659;