8-80643129-C-T

Variant names:

• chr8-80643129-C-T
• rs1462505445
• NM_001033723.3:c.1033G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_001033723.3(ZNF704):​c.1033G>A​(p.Val345Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000345 in 1,447,324 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ZNF704 NM_001033723.3 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

Genes affected

ZNF704 (HGNC:32291): (zinc finger protein 704) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF704	NM_001033723.3	c.1033G>A	p.Val345Met	missense_variant, splice_region_variant	Exon 8 of 9	ENST00000327835.7	NP_001028895.1
ZNF704	NM_001367783.1	c.1555G>A	p.Val519Met	missense_variant, splice_region_variant	Exon 8 of 9		NP_001354712.1
ZNF704	XM_017013725.2	c.1057G>A	p.Val353Met	missense_variant, splice_region_variant	Exon 8 of 9		XP_016869214.1
ZNF704	XR_928797.3	n.1979G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF704	ENST00000327835.7	c.1033G>A	p.Val345Met	missense_variant, splice_region_variant	Exon 8 of 9	1	NM_001033723.3	ENSP00000331462.3
ZNF704	ENST00000519936.2	c.1555G>A	p.Val519Met	missense_variant, splice_region_variant	Exon 8 of 9	5		ENSP00000427715.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1447324 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 719392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1033G>A (p.V345M) alteration is located in exon 8 (coding exon 7) of the ZNF704 gene. This alteration results from a G to A substitution at nucleotide position 1033, causing the valine (V) at amino acid position 345 to be replaced by a methionine (M). 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	0.16
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.21
Sift	Benign	0.034	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.081		Loss of catalytic residue at V345 (P = 0.1095);
MVP		0.10
MPC		1.6
ClinPred		0.87	D
GERP RS		6.0
Varity_R		0.074
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.12		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: rs1462505445; hg19: chr8-81555364;