Genetic Variant NM_207356.3:c.44G>C (chr1-3892968-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_207356.3(C1orf174):c.44G>C(p.Arg15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

C1orf174
NM_207356.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.99

Publications

0 publications found

Variant links:

Genes affected

C1orf174 (HGNC:27915): (chromosome 1 open reading frame 174) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

C1orf174 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207356.3. 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
	C1orf174	NM_207356.3	MANE Select	c.44G>C	p.Arg15Pro	missense	Exon 2 of 4	NP_997239.2	Q8IYL3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1orf174	ENST00000361605.4	TSL:1 MANE Select	c.44G>C	p.Arg15Pro	missense	Exon 2 of 4	ENSP00000355306.3	Q8IYL3
C1orf174	ENST00000680535.1		c.44G>C	p.Arg15Pro	missense	Exon 2 of 3	ENSP00000504980.1	A0A7P0T887
C1orf174	ENST00000680169.1		c.-491G>C		5_prime_UTR	Exon 2 of 4	ENSP00000506016.1	A0A7P0Z4H8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727184

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:

33478

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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

Uncertain

0.52

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.80

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.1

PhyloP100

3.0

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.28

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.81

MutPred

0.45

Loss of methylation at R15 (P = 0.0202)

MVP

0.65

MPC

0.76

ClinPred

0.99

GERP RS

4.3

Varity_R

0.88

gMVP

0.070

Mutation Taster

=65/35

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