8-7359642-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164457.3(ZNF705G):c.295G>C(p.Asp99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 38)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZNF705G NM_001164457.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.423

Genes affected

ZNF705G (HGNC:37134): (zinc finger protein 705G) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08698779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF705G	NM_001164457.3	c.295G>C	p.Asp99His	missense_variant	6/7	ENST00000400156.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF705G	ENST00000400156.4	c.295G>C	p.Asp99His	missense_variant	6/7	2	NM_001164457.3	P1

Frequencies

GnomAD3 genomes Cov.: 38

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457186 Hom.: 0 Cov.: 58 AF XY: 0.00 AC XY: 0 AN XY: 725024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 38

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.295G>C (p.D99H) alteration is located in exon 4 (coding exon 4) of the ZNF705G gene. This alteration results from a G to C substitution at nucleotide position 295, causing the aspartic acid (D) at amino acid position 99 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.00042	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.039
Sift	Benign	0.16	T
Sift4G	Benign	0.41	T
Vest4		0.24
MutPred		0.18		Gain of MoRF binding (P = 0.0423);
MVP		0.13
MPC		0.0011
ClinPred		0.11	T
GERP RS		0.86
Varity_R		0.044
gMVP		0.025

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

Publications

LitVar

Other links and lift over

dbSNP: rs1207837710; hg19: chr8-7217164;