chr8-80641419-T-C

Position:

• chr8-80641419-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001033723.3(ZNF704):​c.1186A>G​(p.Met396Val) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,456,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ZNF704 NM_001033723.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

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]

ZNF704 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28317505).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF704	NM_001033723.3	c.1186A>G	p.Met396Val	missense_variant	9/9	ENST00000327835.7	NP_001028895.1
ZNF704	NM_001367783.1	c.1708A>G	p.Met570Val	missense_variant	9/9		NP_001354712.1
ZNF704	XM_017013725.2	c.1210A>G	p.Met404Val	missense_variant	9/9		XP_016869214.1
ZNF704	XR_928797.3	n.2132A>G		non_coding_transcript_exon_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF704	ENST00000327835.7	c.1186A>G	p.Met396Val	missense_variant	9/9	1	NM_001033723.3	ENSP00000331462.3
ZNF704	ENST00000519936.2	c.1708A>G	p.Met570Val	missense_variant	9/9	5		ENSP00000427715.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1456352 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 724570

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 31

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

Feb 26, 2024

The c.1186A>G (p.M396V) alteration is located in exon 9 (coding exon 8) of the ZNF704 gene. This alteration results from a A to G substitution at nucleotide position 1186, causing the methionine (M) at amino acid position 396 to be replaced by a valine (V). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Benign	0.070	T
Polyphen		0.0040	B
Vest4		0.52
MutPred		0.35		Loss of disorder (P = 0.0707);
MVP		0.14
MPC		0.64
ClinPred		0.62	D
GERP RS		2.0
Varity_R		0.22
gMVP		0.75

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: rs748490553; hg19: chr8-81553654;