11-74634505-T-G

Variant names:

• chr11-74634505-T-G
• rs3824999
• NM_006591.3:c.1007-78T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006591.3(POLD3):​c.1007-78T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 804,116 control chromosomes in the GnomAD database, including 87,844 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (13753 hom., cov: 31)
  • Exomes 𝑓: 0.47 (74091 hom.)
• Consequence: POLD3 NM_006591.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0740
• Publications: 77 publications found

Genes affected

POLD3 (HGNC:20932): (DNA polymerase delta 3, accessory subunit) This gene encodes the 66-kDa 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. The encoded protein plays a role in regulating the activity of DNA polymerase delta through interactions with other subunits and the processivity cofactor proliferating cell nuclear antigen (PCNA). Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]

POLD3 Gene-Disease associations (from GenCC):

• hearing loss disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006591.3. 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
	POLD3	NM_006591.3	MANE Select	c.1007-78T>G		intron	N/A	NP_006582.1
	POLD3	NM_001363597.2		c.890-78T>G		intron	N/A	NP_001350526.1
	POLD3	NR_046409.2		n.981-78T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD3	ENST00000263681.7	TSL:1 MANE Select	c.1007-78T>G		intron	N/A	ENSP00000263681.2
	POLD3	ENST00000527458.5	TSL:1	c.890-78T>G		intron	N/A	ENSP00000432951.1
	POLD3	ENST00000532497.5	TSL:1	c.689-78T>G		intron	N/A	ENSP00000436018.1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60678 AN: 151920 Hom.: 13758 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.468 AC: 305188 AN: 652078 Hom.: 74091 AF XY: 0.467 AC XY: 163121 AN XY: 349386

African (AFR) AF: 0.172 AC: 3117 AN: 18076

American (AMR) AF: 0.337 AC: 13362 AN: 39618

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 12018 AN: 19892

East Asian (EAS) AF: 0.414 AC: 14339 AN: 34604

South Asian (SAS) AF: 0.354 AC: 23535 AN: 66466

European-Finnish (FIN) AF: 0.489 AC: 24321 AN: 49770

Middle Eastern (MID) AF: 0.479 AC: 1962 AN: 4092

European-Non Finnish (NFE) AF: 0.510 AC: 197151 AN: 386438

Other (OTH) AF: 0.464 AC: 15383 AN: 33122

GnomAD4 genome AF: 0.399 AC: 60686 AN: 152038 Hom.: 13753 Cov.: 31 AF XY: 0.399 AC XY: 29642 AN XY: 74318

African (AFR) AF: 0.175 AC: 7267 AN: 41504

American (AMR) AF: 0.402 AC: 6134 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2144 AN: 3470

East Asian (EAS) AF: 0.401 AC: 2076 AN: 5178

South Asian (SAS) AF: 0.349 AC: 1681 AN: 4814

European-Finnish (FIN) AF: 0.492 AC: 5194 AN: 10564

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34697 AN: 67936

Other (OTH) AF: 0.417 AC: 878 AN: 2104

Alfa AF: 0.459 Hom.: 27946

Bravo AF: 0.381

Asia WGS AF: 0.333 AC: 1161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.62
PhyloP100		0.074
Mutation Taster		=100/0	polymorphism (auto)

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: rs3824999; hg19: chr11-74345550; COSMIC: COSV55245928; COSMIC: COSV55245928;