rs751903034

Variant names:

• chr11-67352011-T-A
• rs751903034
• NM_021173.5:c.308A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-67352011-T-A
• chr11-67352011-T-C
• chr11-67352011-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021173.5(POLD4):​c.308A>T​(p.His103Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000101 in 989,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H103R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: POLD4 NM_021173.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59
• Publications: 0 publications found

Genes affected

POLD4 (HGNC:14106): (DNA polymerase delta 4, accessory subunit) This gene encodes the smallest 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 enhances the activity of DNA polymerase delta and plays a role in fork repair and stabilization through interactions with the DNA helicase Bloom syndrome protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

ENSG00000256514 (HGNC:):

RAD9A (HGNC:9827): (RAD9 checkpoint clamp component A) This gene product is highly similar to Schizosaccharomyces pombe rad9, a cell cycle checkpoint protein required for cell cycle arrest and DNA damage repair. This protein possesses 3' to 5' exonuclease activity, which may contribute to its role in sensing and repairing DNA damage. It forms a checkpoint protein complex with RAD1 and HUS1. This complex is recruited by checkpoint protein RAD17 to the sites of DNA damage, which is thought to be important for triggering the checkpoint-signaling cascade. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021173.5. 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
	POLD4	NM_021173.5	MANE Select	c.308A>T	p.His103Leu	missense	Exon 4 of 4	NP_066996.3
	POLD4	NM_001256870.2		c.196A>T	p.Ile66Phe	missense	Exon 3 of 3	NP_001243799.1	Q9HCU8-2
	POLD4	NR_046411.2		n.464A>T		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD4	ENST00000312419.8	TSL:1 MANE Select	c.308A>T	p.His103Leu	missense	Exon 4 of 4	ENSP00000311368.3	Q9HCU8-1
	ENSG00000256514	ENST00000543494.1	TSL:3	c.227A>T	p.His76Leu	missense	Exon 4 of 4	ENSP00000480527.1	A0A087WWV3
	POLD4	ENST00000530584.5	TSL:1	c.83A>T	p.His28Leu	missense	Exon 4 of 4	ENSP00000436361.2	E9PL15

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 989522 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 492944

African (AFR) AF: 0.00 AC: 0 AN: 22116

American (AMR) AF: 0.00 AC: 0 AN: 32976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15142

East Asian (EAS) AF: 0.00 AC: 0 AN: 15184

South Asian (SAS) AF: 0.00 AC: 0 AN: 75012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 758146

Other (OTH) AF: 0.0000273 AC: 1 AN: 36582

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.047	T
Eigen	Benign	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.92	T
PhyloP100		3.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.19
Sift	Benign	0.22	T
Sift4G	Uncertain	0.043	D
Polyphen		0.19	B
Vest4		0.60
MutPred		0.66		Gain of stability (P = 0.0242)
MVP		0.47
MPC		0.77
ClinPred		0.84	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.66
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs751903034; hg19: chr11-67119482;