8-37696011-G-A

Position:

• chr8-37696011-G-A

Variant summary

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

The NM_025069.3(ZNF703):​c.32G>A​(p.Arg11Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,372,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ZNF703 NM_025069.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

Genes affected

ZNF703 (HGNC:25883): (zinc finger protein 703) Predicted to enable DNA-binding transcription factor binding activity. Involved in several processes, including cellular response to estradiol stimulus; mammary gland epithelial cell differentiation; and positive regulation of mammary gland epithelial cell proliferation. Located in cytoplasm and nuclear matrix. Part of protein-containing complex. [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=0.16032174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF703	NM_025069.3	c.32G>A	p.Arg11Lys	missense_variant	1/2	ENST00000331569.6	NP_079345.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF703	ENST00000331569.6	c.32G>A	p.Arg11Lys	missense_variant	1/2	1	NM_025069.3	ENSP00000332325.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1372972 Hom.: 0 Cov.: 36 AF XY: 0.00000295 AC XY: 2 AN XY: 677418

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: 0.00000282

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 24, 2021

The c.32G>A (p.R11K) alteration is located in exon 1 (coding exon 1) of the ZNF703 gene. This alteration results from a G to A substitution at nucleotide position 32, causing the arginine (R) at amino acid position 11 to be replaced by a lysine (K). 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	0.21
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.077
Sift	Benign	0.26	T
Sift4G	Benign	0.97	T
Polyphen		0.011	B
Vest4		0.14
MutPred		0.30		Gain of ubiquitination at R11 (P = 0.0075);
MVP		0.47
ClinPred		0.22	T
GERP RS		2.5
Varity_R		0.14
gMVP		0.34

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: rs1802061242; hg19: chr8-37553529;