1-11786602-A-ATT

Variant names:

• chr1-11786602-A-ATT
• rs55780505
• NM_005957.5:c.*4076_*4077dupAA

Variant summary

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

The NM_001330358.2(MTHFR):​c.*4076_*4077dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1242 hom., cov: 0)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: MTHFR NM_001330358.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 = 0.165 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.*4076_*4077dupAA		3_prime_UTR	Exon 12 of 12	NP_005948.3
	C1orf167	NM_001010881.2	MANE Select	c.3568-768_3568-767dupTT		intron	N/A	NP_001010881.1
	MTHFR	NM_001330358.2		c.*4076_*4077dupAA		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.*4076_*4077dupAA		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3
	MTHFR	ENST00000376592.6	TSL:1	c.*4076_*4077dupAA		3_prime_UTR	Exon 12 of 12	ENSP00000365777.1
	C1orf167	ENST00000688073.1	MANE Select	c.3568-768_3568-767dupTT		intron	N/A	ENSP00000510540.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 16356 AN: 141838 Hom.: 1244 Cov.: 0

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.0875

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0867

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.250 AC: 1 AN: 4

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.115 AC: 16341 AN: 141868 Hom.: 1242 Cov.: 0 AF XY: 0.112 AC XY: 7674 AN XY: 68236

African (AFR) AF: 0.0277 AC: 1072 AN: 38634

American (AMR) AF: 0.0874 AC: 1248 AN: 14278

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 723 AN: 3354

East Asian (EAS) AF: 0.0870 AC: 415 AN: 4770

South Asian (SAS) AF: 0.176 AC: 767 AN: 4368

European-Finnish (FIN) AF: 0.131 AC: 1034 AN: 7916

Middle Eastern (MID) AF: 0.189 AC: 51 AN: 270

European-Non Finnish (NFE) AF: 0.162 AC: 10612 AN: 65430

Other (OTH) AF: 0.127 AC: 249 AN: 1962

Alfa AF: 0.119 Hom.: 551

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neural tube defects, folate-sensitive (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;