Genetic Variant C1orf115:p.Ser87Arg (chr1-220690663-C-A) – 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_024709.5(C1orf115):c.261C>A(p.Ser87Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S87N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

C1orf115
NM_024709.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.10

Publications

0 publications found

Variant links:

Genes affected

C1orf115 (HGNC:25873): (chromosome 1 open reading frame 115) Located in 9+0 non-motile cilium. [provided by Alliance of Genome Resources, Apr 2022]

C1orf115 links:

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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=0.057918966).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024709.5. 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
	C1orf115	NM_024709.5	MANE Select	c.261C>A	p.Ser87Arg	missense	Exon 1 of 2	NP_078985.3	Q9H7X2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf115	ENST00000294889.6	TSL:1 MANE Select	c.261C>A	p.Ser87Arg	missense	Exon 1 of 2	ENSP00000294889.5	Q9H7X2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441722

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716014

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32082

American (AMR)

AF:

0.00

AC:

AN:

42824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25670

East Asian (EAS)

AF:

0.00

AC:

AN:

38052

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5262

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103778

Other (OTH)

AF:

0.00

AC:

AN:

59520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.38

M_CAP

Benign

0.024

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PhyloP100

-1.1

PROVEAN

Benign

-1.9

REVEL

Benign

0.15

Sift

Uncertain

0.015

Sift4G

Uncertain

0.019

Polyphen

0.0010

Vest4

0.034

MutPred

0.21

Gain of solvent accessibility (P = 0.0155)

MVP

0.014

MPC

0.52

ClinPred

0.22

GERP RS

1.5

PromoterAI

0.0062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.054

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over