rs3737967

Variant names:

• chr1-11787392-G-A
• rs3737967
• NM_001010881.2:c.3572G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11787392-G-A
• chr1-11787392-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001010881.2(C1orf167):​c.3572G>A​(p.Arg1191His) variant causes a missense 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. 13/19 in silico tools predict 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: C1orf167 NM_001010881.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• Publications: 35 publications found

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]

MTHFR Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
C1orf167	NM_001010881.2	c.3572G>A	p.Arg1191His	missense_variant	Exon 17 of 21	ENST00000688073.1	NP_001010881.1
MTHFR	NM_005957.5	c.*3288C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000376590.9	NP_005948.3

Ensembl

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

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

GnomAD2 exomes AF: 0.0570 AC: 8158 AN: 143132 AF XY: 0.0613

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 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

African (AFR) AF: 0.0254 AC: 611 AN: 24090

American (AMR) AF: 0.0422 AC: 1126 AN: 26696

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 269 AN: 15440

East Asian (EAS) AF: 0.118 AC: 1464 AN: 12436

South Asian (SAS) AF: 0.127 AC: 9515 AN: 75056

European-Finnish (FIN) AF: 0.0176 AC: 462 AN: 26244

Middle Eastern (MID) AF: 0.0200 AC: 86 AN: 4310

European-Non Finnish (NFE) AF: 0.0501 AC: 45788 AN: 914632

Other (OTH) AF: 0.0619 AC: 2536 AN: 40974

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

African (AFR) AF: 0.0304 AC: 1265 AN: 41544

American (AMR) AF: 0.0430 AC: 658 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3468

East Asian (EAS) AF: 0.119 AC: 616 AN: 5180

South Asian (SAS) AF: 0.149 AC: 717 AN: 4826

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0460 AC: 3130 AN: 68014

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0451 Hom.: 539

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
PhyloP100		-1.7
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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