8-119847074-T-C

Position:

• chr8-119847074-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024094.3(DSCC1):​c.493A>G​(p.Thr165Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSCC1 NM_024094.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.56

Genes affected

DSCC1 (HGNC:24453): (DNA replication and sister chromatid cohesion 1) CHTF18 (MIM 613201), CHTF8 (MIM 613202), and DSCC1 are components of an alternative replication factor C (RFC) (see MIM 600404) complex that loads PCNA (MIM 176740) onto DNA during S phase of the cell cycle (Merkle et al., 2003 [PubMed 12766176]; Bermudez et al., 2003 [PubMed 12930902]).[supplied by OMIM, Dec 2009]

ENSG00000286362 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2970687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSCC1	NM_024094.3	c.493A>G	p.Thr165Ala	missense_variant	4/9	ENST00000313655.5	NP_076999.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSCC1	ENST00000313655.5	c.493A>G	p.Thr165Ala	missense_variant	4/9	1	NM_024094.3	ENSP00000322180.4
ENSG00000286362	ENST00000665858.1	n.203-7601T>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460298 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

The c.493A>G (p.T165A) alteration is located in exon 4 (coding exon 4) of the DSCC1 gene. This alteration results from a A to G substitution at nucleotide position 493, causing the threonine (T) at amino acid position 165 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.17
Sift	Benign	0.35	T
Sift4G	Benign	0.20	T
Polyphen		0.41	B
Vest4		0.45
MutPred		0.50		Loss of phosphorylation at T165 (P = 0.0084);
MVP		0.47
MPC		0.40
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.083
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-120859314;