Genetic Variant NM_001010881.2:c.3572G>T (chr1-11787392-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001010881.2(C1orf167):c.3572G>T(p.Arg1191Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000877 in 1,140,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: not found (cov: 33)

Exomes 𝑓: 8.8e-7 ( 0 hom. )

Consequence

C1orf167
NM_001010881.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.70

Publications

0 publications found

Variant links:

Genes affected

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

C1orf167 links:

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

MTHFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0359779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1orf167	NM_001010881.2 link	c.3572G>T	p.Arg1191Leu	missense_variant	Exon 17 of 21	ENST00000688073.1	NP_001010881.1
MTHFR	NM_005957.5 link	c.*3288C>A		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 link	c.3572G>T	p.Arg1191Leu	missense_variant	Exon 17 of 21		NM_001010881.2	ENSP00000510540.1
MTHFR	ENST00000376590.9 link	c.*3288C>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.77e-7

AC:

AN:

1140174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

558312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24098

American (AMR)

AF:

0.00

AC:

AN:

26712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15440

East Asian (EAS)

AF:

0.00

AC:

AN:

12448

South Asian (SAS)

AF:

0.00

AC:

AN:

75096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4310

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

914834

Other (OTH)

AF:

0.00

AC:

AN:

40988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.0070

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.0053

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.37

M_CAP

Benign

0.0038

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

-1.7

PROVEAN

Benign

-1.0

REVEL

Benign

0.11

Sift

Benign

0.066

Sift4G

Benign

0.25

Vest4

0.19

ClinPred

0.11

GERP RS

-7.5

Varity_R

0.044

gMVP

0.095

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over