chr6-43576213-C-A

Variant names:

• chr6-43576213-C-A
• rs542595870
• NM_006502.3:c.-232C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_006502.3(POLH):​c.-232C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 209,464 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: POLH NM_006502.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.53
• Publications: 0 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]

XPO5 (HGNC:17675): (exportin 5) This gene encodes a member of the karyopherin family that is required for the transport of small RNAs and double-stranded RNA-binding proteins from the nucleus to the cytoplasm. The encoded protein translocates cargo through the nuclear pore complex in a RanGTP-dependent process. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00223 (339/152346) while in subpopulation NFE AF = 0.0005 (34/68034). AF 95% confidence interval is 0.000367. There are 6 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 6 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.-232C>A		5_prime_UTR	Exon 1 of 11	NP_006493.1	Q9Y253-1
	POLH	NM_001291969.2		c.-245C>A		5_prime_UTR	Exon 1 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.-232C>A		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.-232C>A		5_prime_UTR	Exon 1 of 11	ENSP00000361310.4	Q9Y253-1
	POLH	ENST00000953718.1		c.-232C>A		5_prime_UTR	Exon 1 of 10	ENSP00000623777.1
	POLH	ENST00000901658.1		c.-232C>A		5_prime_UTR	Exon 1 of 10	ENSP00000571717.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152228 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00203 AC: 116 AN: 57118 Hom.: 3 Cov.: 0 AF XY: 0.00187 AC XY: 54 AN XY: 28896

African (AFR) AF: 0.00 AC: 0 AN: 1446

American (AMR) AF: 0.00 AC: 0 AN: 950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2046

East Asian (EAS) AF: 0.00 AC: 0 AN: 2488

South Asian (SAS) AF: 0.00 AC: 0 AN: 4482

European-Finnish (FIN) AF: 0.0216 AC: 78 AN: 3610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000660 AC: 25 AN: 37872

Other (OTH) AF: 0.00332 AC: 13 AN: 3914

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152346 Hom.: 6 Cov.: 33 AF XY: 0.00319 AC XY: 238 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0283 AC: 301 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000174

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.75
CADD	Benign	0.075
DANN	Benign	0.58
PhyloP100		-3.5
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs542595870; hg19: chr6-43543950;