1-247301075-T-C

Variant names:

• chr1-247301075-T-C
• rs140317681
• NM_032752.3:c.1208A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_032752.3(ZNF496):​c.1208A>G​(p.Lys403Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,626 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: ZNF496 NM_032752.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0100

Genes affected

ZNF496 (HGNC:23713): (zinc finger protein 496) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and protein self-association. Predicted to be involved in positive regulation of transcription, DNA-templated and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Predicted to be located in nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity ZN496_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.023583353).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF496	NM_032752.3	c.1208A>G	p.Lys403Arg	missense_variant	Exon 10 of 10	ENST00000682384.1	NP_116141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF496	ENST00000682384.1	c.1208A>G	p.Lys403Arg	missense_variant	Exon 10 of 10		NM_032752.3	ENSP00000507236.1
ZNF496	ENST00000294753.8	c.1208A>G	p.Lys403Arg	missense_variant	Exon 9 of 9	1		ENSP00000294753.4
ZNF496	ENST00000461277.2	c.983A>G	p.Lys328Arg	missense_variant	Exon 8 of 8	1		ENSP00000473324.1
ZNF496	ENST00000462139.1	n.5580A>G		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000159 AC: 40 AN: 250886 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135802

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000181 AC: 264 AN: 1461414 Hom.: 2 Cov.: 31 AF XY: 0.000199 AC XY: 145 AN XY: 727028

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1208A>G (p.K403R) alteration is located in exon 9 (coding exon 7) of the ZNF496 gene. This alteration results from a A to G substitution at nucleotide position 1208, causing the lysine (K) at amino acid position 403 to be replaced by an arginine (R). 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	0.089
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.9
DANN	Benign	0.33
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.86	L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.36	N;.
REVEL	Benign	0.030
Sift	Benign	0.49	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.043
MVP		0.34
MPC		0.35
ClinPred		0.024	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.44

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: rs140317681; hg19: chr1-247464377;