19-50415765-A-T

Position:

• chr19-50415765-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002691.4(POLD1):​c.2759A>T​(p.Asp920Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D920E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2759A>T	p.Asp920Val	missense_variant	22/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2759A>T	p.Asp920Val	missense_variant	22/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	4.8	H;.;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.9	D;.;.;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.96
MutPred		0.81		Gain of MoRF binding (P = 0.0412);.;.;Gain of MoRF binding (P = 0.0412);
MVP		0.73
MPC		1.9
ClinPred		1.0	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50919022;