6-43576328-C-T

Variant names:

• chr6-43576328-C-T
• rs56300149
• NM_006502.3:c.-117C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006502.3(POLH):​c.-117C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00584 in 152,330 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLH NM_006502.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.152
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-43576328-C-T is Benign according to our data. Variant chr6-43576328-C-T is described in ClinVar as Benign. ClinVar VariationId is 356893.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00584 (890/152330) while in subpopulation AFR AF = 0.0201 (837/41574). AF 95% confidence interval is 0.019. There are 11 homozygotes in GnomAd4. There are 428 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.-117C>T		5_prime_UTR	Exon 1 of 11	NP_006493.1	Q9Y253-1
	POLH	NM_001291969.2		c.-130C>T		5_prime_UTR	Exon 1 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.-117C>T		5_prime_UTR	Exon 1 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.-117C>T		5_prime_UTR	Exon 1 of 11	ENSP00000361310.4	Q9Y253-1
	POLH	ENST00000372226.1	TSL:1	c.-117C>T		5_prime_UTR	Exon 1 of 11	ENSP00000361300.1	Q9Y253-2
	POLH	ENST00000921322.1		c.-117C>T		5_prime_UTR	Exon 2 of 12	ENSP00000591381.1

Frequencies

GnomAD3 genomes AF: 0.00584 AC: 889 AN: 152212 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1086 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 562

African (AFR) AF: 0.00 AC: 0 AN: 46

American (AMR) AF: 0.00 AC: 0 AN: 10

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 52

East Asian (EAS) AF: 0.00 AC: 0 AN: 24

South Asian (SAS) AF: 0.00 AC: 0 AN: 32

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828

Other (OTH) AF: 0.00 AC: 0 AN: 50

GnomAD4 genome AF: 0.00584 AC: 890 AN: 152330 Hom.: 11 Cov.: 33 AF XY: 0.00575 AC XY: 428 AN XY: 74482

African (AFR) AF: 0.0201 AC: 837 AN: 41574

American (AMR) AF: 0.00255 AC: 39 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00157 Hom.: 1

Bravo AF: 0.00628

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Xeroderma pigmentosum variant type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.3
DANN	Benign	0.82
PhyloP100		0.15
PromoterAI		-0.0052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs56300149; hg19: chr6-43544065;