6-43605330-C-T

Variant names:

• chr6-43605330-C-T
• rs376447275
• NM_006502.3:c.1074+11C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006502.3(POLH):​c.1074+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLH NM_006502.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.425
• 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]

GTPBP2 (HGNC:4670): (GTP binding protein 2) GTP-binding proteins, or G proteins, constitute a superfamily capable of binding GTP or GDP. G proteins are activated by binding GTP and are inactivated by hydrolyzing GTP to GDP. This general mechanism enables G proteins to perform a wide range of biologic activities.[supplied by OMIM, Jan 2003]

GTPBP2 Gene-Disease associations (from GenCC):

• Jaberi-Elahi syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-43605330-C-T is Benign according to our data. Variant chr6-43605330-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3645467.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1074+11C>T		intron	N/A	NP_006493.1	Q9Y253-1
	POLH	NM_001291969.2		c.702+11C>T		intron	N/A	NP_001278898.1
	POLH	NM_001291970.2		c.1074+11C>T		intron	N/A	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.1074+11C>T		intron	N/A	ENSP00000361310.4	Q9Y253-1
	POLH	ENST00000372226.1	TSL:1	c.1074+11C>T		intron	N/A	ENSP00000361300.1	Q9Y253-2
	POLH	ENST00000921322.1		c.1074+11C>T		intron	N/A	ENSP00000591381.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 242228 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1362438 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 683086

African (AFR) AF: 0.00 AC: 0 AN: 31572

American (AMR) AF: 0.00 AC: 0 AN: 44118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 39042

South Asian (SAS) AF: 0.00 AC: 0 AN: 83372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1023416

Other (OTH) AF: 0.00 AC: 0 AN: 56888

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.6
DANN	Benign	0.80
PhyloP100		-0.42

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: rs376447275; hg19: chr6-43573067;