chr19-50416622-C-G

Position:

• chr19-50416622-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002691.4(POLD1):​c.2966C>G​(p.Thr989Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,411,024 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. Synonymous variant affecting the same amino acid position (i.e. T989T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15

Genes affected

POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

ENSG00000142539 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2966C>G	p.Thr989Arg	missense_variant	24/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2966C>G	p.Thr989Arg	missense_variant	24/27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.173C>G	p.Thr58Arg	missense_variant	3/10	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1411024 Hom.: 0 Cov.: 34 AF XY: 0.00000143 AC XY: 1 AN XY: 698400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	4.3	H;.;.;H
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.9	D;.;.;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.62
MutPred		0.61		Gain of MoRF binding (P = 0.0073);.;.;Gain of MoRF binding (P = 0.0073);
MVP		0.83
MPC		1.7
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.86
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: chr19-50919879;