rs35675573

Variant names:

• chr6-43604716-C-T
• rs35675573
• NM_006502.3:c.986C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006502.3(POLH):​c.986C>T​(p.Thr329Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000996 in 1,614,090 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (5 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.69
• Publications: 6 publications found

Genes affected

POLH (HGNC:9181): (DNA polymerase eta) This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases. However, it accurately replicates UV-damaged DNA; when thymine dimers are present, this polymerase inserts the complementary nucleotides in the newly synthesized DNA, thereby bypassing the lesion and suppressing the mutagenic effect of UV-induced DNA damage. This polymerase is thought to be involved in hypermutation during immunoglobulin class switch recombination. Mutations in this gene result in XPV, a variant type of xeroderma pigmentosum. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

POLH Gene-Disease associations (from GenCC):

• xeroderma pigmentosum variant type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070595145).
• BP6: Variant 6-43604716-C-T is Benign according to our data. Variant chr6-43604716-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00487 (742/152270) while in subpopulation AFR AF = 0.0162 (674/41548). AF 95% confidence interval is 0.0152. There are 5 homozygotes in GnomAd4. There are 325 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006502.3. 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
	POLH	NM_006502.3	MANE Select	c.986C>T	p.Thr329Ile	missense	Exon 8 of 11	NP_006493.1	Q9Y253-1
	POLH	NM_001291969.2		c.614C>T	p.Thr205Ile	missense	Exon 6 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.986C>T	p.Thr329Ile	missense	Exon 8 of 11	NP_001278899.1	Q9Y253-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	ENST00000372236.9	TSL:1 MANE Select	c.986C>T	p.Thr329Ile	missense	Exon 8 of 11	ENSP00000361310.4	Q9Y253-1
	POLH	ENST00000372226.1	TSL:1	c.986C>T	p.Thr329Ile	missense	Exon 8 of 11	ENSP00000361300.1	Q9Y253-2
	POLH	ENST00000921322.1		c.986C>T	p.Thr329Ile	missense	Exon 9 of 12	ENSP00000591381.1

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 742 AN: 152152 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00139 AC: 349 AN: 251468 AF XY: 0.00101

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000592 AC: 866 AN: 1461820 Hom.: 5 Cov.: 32 AF XY: 0.000502 AC XY: 365 AN XY: 727216

African (AFR) AF: 0.0174 AC: 584 AN: 33478

American (AMR) AF: 0.00168 AC: 75 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1111970

Other (OTH) AF: 0.00136 AC: 82 AN: 60384

GnomAD4 genome AF: 0.00487 AC: 742 AN: 152270 Hom.: 5 Cov.: 32 AF XY: 0.00436 AC XY: 325 AN XY: 74458

African (AFR) AF: 0.0162 AC: 674 AN: 41548

American (AMR) AF: 0.00295 AC: 45 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00212 Hom.: 7

Bravo AF: 0.00582

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Xeroderma pigmentosum variant type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.024	D
Polyphen		0.016	B
Vest4		0.17
MVP		0.71
MPC		0.24
ClinPred		0.038	T
GERP RS		4.9
Varity_R		0.64
gMVP		0.58
Mutation Taster		=58/42	polymorphism

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: rs35675573; hg19: chr6-43572453;