6-158192107-C-G

Variant names:

• chr6-158192107-C-G
• rs121434364
• NM_207118.3:c.166C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_207118.3(GTF2H5):​c.166C>G​(p.Arg56Gly) 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 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R56Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GTF2H5 NM_207118.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49
• Publications: 6 publications found

Genes affected

GTF2H5 (HGNC:21157): (general transcription factor IIH subunit 5) This gene encodes a subunit of transcription/repair factor TFIIH, which functions in gene transcription and DNA repair. This protein stimulates ERCC3/XPB ATPase activity to trigger DNA opening during DNA repair, and is implicated in regulating cellular levels of TFIIH. Mutations in this gene result in trichothiodystrophy, complementation group A. [provided by RefSeq, Mar 2009]

GTF2H5 Gene-Disease associations (from GenCC):

• trichothiodystrophy 3, photosensitive

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.12315 (below the threshold of 3.09). Trascript score misZ: 0.12589 (below the threshold of 3.09). GenCC associations: The gene is linked to trichothiodystrophy 3, photosensitive, trichothiodystrophy.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207118.3. 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
	GTF2H5	NM_207118.3	MANE Select	c.166C>G	p.Arg56Gly	missense	Exon 3 of 3	NP_997001.1	Q6ZYL4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTF2H5	ENST00000607778.2	TSL:1 MANE Select	c.166C>G	p.Arg56Gly	missense	Exon 3 of 3	ENSP00000476100.1	Q6ZYL4
	GTF2H5	ENST00000889639.1		c.283C>G	p.Arg95Gly	missense	Exon 4 of 4	ENSP00000559698.1
	GTF2H5	ENST00000689809.1		c.166C>G	p.Arg56Gly	missense	Exon 4 of 4	ENSP00000510752.1	Q6ZYL4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251418 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 AF: 6.84e-7 AC: 1 AN: 1461386 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727016

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111770

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.11	T
PhyloP100		3.5
PrimateAI	Uncertain	0.75	T
Sift4G	Uncertain	0.012	D
Polyphen		0.90	P
Vest4		0.60
MutPred		0.58		Loss of stability (P = 0.0314)
MVP		0.36
MPC		0.042
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.68
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121434364; hg19: chr6-158613139;