Genetic Variant C1orf167:p.Pro508Leu (chr1-11789386-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000449278.1(C1orf167):c.1523C>T(p.Pro508Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000792 in 1,303,442 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/6 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 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00083 ( 3 hom. )

Consequence

C1orf167
ENST00000449278.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.11

Publications

2 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.005).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1orf167	NM_001010881.2 link	c.4290C>T	p.Ala1430Ala	synonymous_variant	Exon 21 of 21	ENST00000688073.1	NP_001010881.1	Q5SNV9A2VCK6A0A8I5KXP5Q8NDG0
MTHFR	NM_005957.5 link	c.*1294G>A		3_prime_UTR_variant	Exon 12 of 12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1orf167	ENST00000688073.1 link	c.4290C>T	p.Ala1430Ala	synonymous_variant	Exon 21 of 21		NM_001010881.2	ENSP00000510540.1		A0A8I5KXP5
MTHFR	ENST00000376590.9 link	c.*1294G>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.000514

AC:

AN:

151604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000919

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000379

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000707

Gnomad OTH

AF:

0.000483

GnomAD2 exomes

AF:

0.000562

AC:

AN:

149546

AF XY:

0.000534

show subpopulations

Gnomad AFR exome

AF:

0.000444

Gnomad AMR exome

AF:

0.000692

Gnomad ASJ exome

AF:

0.000955

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000450

Gnomad NFE exome

AF:

0.000776

Gnomad OTH exome

AF:

0.000932

GnomAD4 exome

AF:

0.000828

AC:

954

AN:

1151838

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

432

AN XY:

564810

show subpopulations

African (AFR)

AF:

0.000328

AC:

AN:

24414

American (AMR)

AF:

0.000602

AC:

AN:

28262

Ashkenazi Jewish (ASJ)

AF:

0.000816

AC:

AN:

15934

East Asian (EAS)

AF:

0.00

AC:

AN:

12844

South Asian (SAS)

AF:

0.0000394

AC:

AN:

76194

European-Finnish (FIN)

AF:

0.000329

AC:

AN:

27338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4324

European-Non Finnish (NFE)

AF:

0.000959

AC:

883

AN:

920920

Other (OTH)

AF:

0.000505

AC:

AN:

41608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

112

168

224

280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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

AF:

0.000514

AC:

AN:

151604

Hom.:

Cov.:

AF XY:

0.000621

AC XY:

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.000170

AC:

AN:

41226

American (AMR)

AF:

0.000919

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.000379

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000707

AC:

AN:

67886

Other (OTH)

AF:

0.000483

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000701

Hom.:

Bravo

AF:

0.000642

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.35

(source)

DANN

Benign

0.90

PhyloP100

-3.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over