6-43614198-A-T

Variant names:

• chr6-43614198-A-T
• rs9333555
• NM_006502.3:c.1783A>T

Variant summary

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

The NM_006502.3(POLH):​c.1783A>T​(p.Met595Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M595V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.645
• 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, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042023808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLH	NM_006502.3	c.1783A>T	p.Met595Leu	missense_variant	Exon 11 of 11	ENST00000372236.9	NP_006493.1
POLH	NM_001291969.2	c.1411A>T	p.Met471Leu	missense_variant	Exon 9 of 9		NP_001278898.1
POLH	XM_047418900.1	c.1327A>T	p.Met443Leu	missense_variant	Exon 8 of 8		XP_047274856.1
POLH	NM_001291970.2	c.*467A>T		3_prime_UTR_variant	Exon 11 of 11		NP_001278899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLH	ENST00000372236.9	c.1783A>T	p.Met595Leu	missense_variant	Exon 11 of 11	1	NM_006502.3	ENSP00000361310.4
POLH	ENST00000372226.1	c.*467A>T		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000361300.1
GTPBP2	ENST00000496137.5	n.*131+5921T>A		intron_variant	Intron 3 of 3	3		ENSP00000436973.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461108 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726688

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111340

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.078
DANN	Benign	0.60
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L
PhyloP100		-0.65
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.023
Sift	Benign	0.38	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.23		Loss of helix (P = 0.1299);
MVP		0.38
MPC		0.20
ClinPred		0.053	T
GERP RS		-6.8
Varity_R		0.070
gMVP		0.14
Mutation Taster		=93/7	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: rs9333555; hg19: chr6-43581935;