NM_001039690.5:c.85C>T

Variant names:

• chr16-69121109-G-A
• rs375808540
• NM_001039690.5:c.85C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001039690.5(CHTF8):​c.85C>T​(p.Arg29Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: CHTF8 NM_001039690.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18
• Publications: 1 publications found

Genes affected

CHTF8 (HGNC:24353): (chromosome transmission fidelity factor 8) This gene encodes a short protein that forms part of the Ctf18 replication factor C (RFC) complex that occurs in both yeast and mammals. The heteroheptameric RFC complex plays a role in sister chromatid cohesion and may load the replication clamp PCNA (proliferating cell nuclear antigen) onto DNA during DNA replication and repair. This gene is ubiquitously expressed and has been shown to have reduced expression in renal and prostate tumors. Alternatively spliced transcript variants have been described. This gene has a pseudogene on chromosome X. [provided by RefSeq, Oct 2018]

DERPC (HGNC:54084): (DERPC proline and glycine rich nuclear protein) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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, 0.748

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039690.5. 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
	CHTF8	NM_001039690.5	MANE Select	c.85C>T	p.Arg29Cys	missense	Exon 3 of 4	NP_001034779.1	P0CG13
	DERPC	NM_001002847.4	MANE Select	c.-222+327C>T		intron	N/A	NP_001002847.1	P0CG12
	DERPC	NM_001040144.3		c.-278C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 3	NP_001035234.2	P0CG12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHTF8	ENST00000448552.7	TSL:1 MANE Select	c.85C>T	p.Arg29Cys	missense	Exon 3 of 4	ENSP00000408367.3	P0CG13
	DERPC	ENST00000519520.7	TSL:2 MANE Select	c.-222+327C>T		intron	N/A	ENSP00000427718.2	P0CG12
	CHTF8	ENST00000398235.6	TSL:2	c.85C>T	p.Arg29Cys	missense	Exon 3 of 4	ENSP00000381290.2	P0CG13

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249560 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461598 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74310

African (AFR) AF: 0.0000724 AC: 3 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.78
MPC		1.0
ClinPred		0.94	D
GERP RS		5.6
PromoterAI		-0.014	Neutral
gMVP		0.46
Mutation Taster		=37/63	disease causing

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: rs375808540; hg19: chr16-69155012; COSMIC: COSV54708754; COSMIC: COSV54708754;