rs569629260

Variant names:

• chr1-11787634-C-T
• rs569629260
• NM_005957.5:c.*3046G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005957.5(MTHFR):​c.*3046G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 806,676 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (11 hom.)
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• 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]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00266 (406/152356) while in subpopulation NFE AF = 0.00509 (346/68024). AF 95% confidence interval is 0.00464. There are 3 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.*3046G>A		3_prime_UTR	Exon 12 of 12	NP_005948.3
	C1orf167	NM_001010881.2	MANE Select	c.3673+141C>T		intron	N/A	NP_001010881.1	Q5SNV9-1
	MTHFR	NM_001330358.2		c.*3046G>A		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.*3046G>A		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000376592.6	TSL:1	c.*3046G>A		3_prime_UTR	Exon 12 of 12	ENSP00000365777.1	P42898-1
	C1orf167	ENST00000688073.1	MANE Select	c.3673+141C>T		intron	N/A	ENSP00000510540.1	Q5SNV9-1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152238 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00452 AC: 2956 AN: 654320 Hom.: 11 Cov.: 9 AF XY: 0.00449 AC XY: 1444 AN XY: 321636

African (AFR) AF: 0.000377 AC: 5 AN: 13274

American (AMR) AF: 0.00174 AC: 16 AN: 9192

Ashkenazi Jewish (ASJ) AF: 0.000293 AC: 2 AN: 6824

East Asian (EAS) AF: 0.00 AC: 0 AN: 8530

South Asian (SAS) AF: 0.00149 AC: 73 AN: 48980

European-Finnish (FIN) AF: 0.00224 AC: 24 AN: 10694

Middle Eastern (MID) AF: 0.000341 AC: 1 AN: 2936

European-Non Finnish (NFE) AF: 0.00517 AC: 2739 AN: 529990

Other (OTH) AF: 0.00402 AC: 96 AN: 23900

GnomAD4 genome AF: 0.00266 AC: 406 AN: 152356 Hom.: 3 Cov.: 33 AF XY: 0.00242 AC XY: 180 AN XY: 74502

African (AFR) AF: 0.000553 AC: 23 AN: 41588

American (AMR) AF: 0.000392 AC: 6 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4834

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00503 Hom.: 1

Bravo AF: 0.00254

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.63
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs569629260; hg19: chr1-11847691;