17-8248029-G-C

Variant names:

• chr17-8248029-G-C
• rs923853643
• NM_025099.6:c.8C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025099.6(CTC1):​c.8C>G​(p.Ala3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 146,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTC1 NM_025099.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.512
• Publications: 1 publications found

Genes affected

CTC1 (HGNC:26169): (CST telomere replication complex component 1) This gene encodes a component of the CST complex. This complex plays an essential role in protecting telomeres from degradation. This protein also forms a heterodimer with the CST complex subunit STN1 to form the enzyme alpha accessory factor. This enzyme regulates DNA replication. Mutations in this gene are the cause of cerebroretinal microangiopathy with calcifications and cysts. Alternate splicing results in both coding and non-coding variants. [provided by RefSeq, Mar 2012]

PFAS (HGNC:8863): (phosphoribosylformylglycinamidine synthase) Purines are necessary for many cellular processes, including DNA replication, transcription, and energy metabolism. Ten enzymatic steps are required to synthesize inosine monophosphate (IMP) in the de novo pathway of purine biosynthesis. The enzyme encoded by this gene catalyzes the fourth step of IMP biosynthesis. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.058300376).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025099.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	NM_025099.6	MANE Select	c.8C>G	p.Ala3Gly	missense	Exon 1 of 23	NP_079375.3
	CTC1	NM_001411067.1		c.8C>G	p.Ala3Gly	missense	Exon 1 of 21	NP_001397996.1
	CTC1	NR_046431.2		n.28C>G		non_coding_transcript_exon	Exon 1 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTC1	ENST00000651323.1	MANE Select	c.8C>G	p.Ala3Gly	missense	Exon 1 of 23	ENSP00000498499.1
	CTC1	ENST00000581729.2	TSL:3	c.8C>G	p.Ala3Gly	missense	Exon 1 of 21	ENSP00000462720.2
	CTC1	ENST00000580299.2	TSL:5	c.8C>G	p.Ala3Gly	missense	Exon 1 of 21	ENSP00000462607.2

Frequencies

GnomAD3 genomes AF: 0.0000205 AC: 3 AN: 146526 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000154 AC: 2 AN: 1296974 Hom.: 0 Cov.: 32 AF XY: 0.00000155 AC XY: 1 AN XY: 643158

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

African (AFR) AF: 0.0000347 AC: 1 AN: 28782

American (AMR) AF: 0.00 AC: 0 AN: 39600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20272

East Asian (EAS) AF: 0.00 AC: 0 AN: 24530

South Asian (SAS) AF: 0.00 AC: 0 AN: 84270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4864

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1007478

Other (OTH) AF: 0.0000202 AC: 1 AN: 49546

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000205 AC: 3 AN: 146526 Hom.: 0 Cov.: 30 AF XY: 0.0000280 AC XY: 2 AN XY: 71332

African (AFR) AF: 0.0000749 AC: 3 AN: 40080

American (AMR) AF: 0.00 AC: 0 AN: 14806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4688

South Asian (SAS) AF: 0.00 AC: 0 AN: 4440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66300

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.8
DANN	Benign	0.94
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.51
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.10
Sift	Benign	0.27	T
Sift4G	Benign	0.36	T
Polyphen		0.0020	B
Vest4		0.28
MutPred		0.35		Loss of catalytic residue at M1 (P = 0.0264)
MVP		0.088
MPC		0.12
ClinPred		0.14	T
GERP RS		-1.7
PromoterAI		-0.42	Neutral
Varity_R		0.044
gMVP		0.39
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs923853643; hg19: chr17-8151347;