1-11787392-G-A

Position:

• chr1-11787392-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000376590.9(MTHFR):​c.*3288C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,292,148 control chromosomes in the GnomAD database, including 2,364 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 0.044 (231 hom., cov: 33)
  • Exomes 𝑓: 0.054 (2133 hom.)
• Consequence: MTHFR ENST00000376590.9 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70

Genes affected

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

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012913942).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1orf167	NM_001010881.2	c.3572G>A	p.Arg1191His	missense_variant	17/21	ENST00000688073.1	NP_001010881.1
MTHFR	NM_005957.5	c.*3288C>T		3_prime_UTR_variant	12/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1orf167	ENST00000688073.1	c.3572G>A	p.Arg1191His	missense_variant	17/21		NM_001010881.2	ENSP00000510540	A2
MTHFR	ENST00000376590.9	c.*3288C>T		3_prime_UTR_variant	12/12	1	NM_005957.5	ENSP00000365775	A1

Frequencies

GnomAD3 genomes AF: 0.0442 AC: 6719 AN: 152152 Hom.: 230 Cov.: 33

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0429

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0570 AC: 8158 AN: 143132 Hom.: 399 AF XY: 0.0613 AC XY: 4725 AN XY: 77114

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.0421

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0457

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0543 AC: 61857 AN: 1139878 Hom.: 2133 Cov.: 30 AF XY: 0.0566 AC XY: 31618 AN XY: 558176

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.0422

Gnomad4 ASJ exome AF: 0.0174

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0501

Gnomad4 OTH exome AF: 0.0619

GnomAD4 genome AF: 0.0442 AC: 6723 AN: 152270 Hom.: 231 Cov.: 33 AF XY: 0.0443 AC XY: 3297 AN XY: 74460

Gnomad4 AFR AF: 0.0304

Gnomad4 AMR AF: 0.0430

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.0161

Gnomad4 NFE AF: 0.0460

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0427 Hom.: 221

Bravo AF: 0.0426

TwinsUK AF: 0.0494 AC: 183

ALSPAC AF: 0.0522 AC: 201

ExAC AF: 0.0581 AC: 1256

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.017
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.91	P;P;P;P
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.026
Sift	Benign	0.038	D
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.044
MPC		0.97
ClinPred		0.0096	T
GERP RS		-7.5
Varity_R		0.016
gMVP		0.064

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

Publications

LitVar

Other links and lift over

dbSNP: rs3737967; hg19: chr1-11847449; COSMIC: COSV57172141; COSMIC: COSV57172141;