rs1554140189

Variant names:

• chr6-43597715-CT-C
• rs1554140189
• NM_006502.3:c.512delT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006502.3(POLH):​c.512delT​(p.Leu171TyrfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLH NM_006502.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-43597715-CT-C is Pathogenic according to our data. Variant chr6-43597715-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 520989.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLH	NM_006502.3	c.512delT	p.Leu171TyrfsTer25	frameshift_variant	Exon 5 of 11	ENST00000372236.9	NP_006493.1
POLH	NM_001291969.2	c.140delT	p.Leu47TyrfsTer25	frameshift_variant	Exon 3 of 9		NP_001278898.1
POLH	NM_001291970.2	c.512delT	p.Leu171TyrfsTer25	frameshift_variant	Exon 5 of 11		NP_001278899.1
POLH	XM_047418900.1	c.56delT	p.Leu19TyrfsTer25	frameshift_variant	Exon 2 of 8		XP_047274856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLH	ENST00000372236.9	c.512delT	p.Leu171TyrfsTer25	frameshift_variant	Exon 5 of 11	1	NM_006502.3	ENSP00000361310.4
POLH	ENST00000372226.1	c.512delT	p.Leu171TyrfsTer25	frameshift_variant	Exon 5 of 11	1		ENSP00000361300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Mar 08, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1554140189; hg19: chr6-43565452;