1-90007473-G-A

Position:

• chr1-90007473-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182976.4(ZNF326):​c.338G>A​(p.Ser113Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000014 (0 hom.)
• Consequence: ZNF326 NM_182976.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

Genes affected

ZNF326 (HGNC:14104): (zinc finger protein 326) Enables RNA polymerase II complex binding activity. Involved in regulation of DNA-templated transcription, elongation and regulation of RNA splicing. Located in nucleoplasm. Part of DBIRD complex. [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
• BP4: Computational evidence support a benign effect (MetaRNN=0.06737998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF326	NM_182976.4	c.338G>A	p.Ser113Asn	missense_variant	5/12	ENST00000340281.9	NP_892021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF326	ENST00000340281.9	c.338G>A	p.Ser113Asn	missense_variant	5/12	1	NM_182976.4	ENSP00000340796	P2
ZNF326	ENST00000370447.3	c.210-139G>A		intron_variant		1		ENSP00000359476	A2
ZNF326	ENST00000394583.7	c.151+2381G>A		intron_variant, NMD_transcript_variant		1		ENSP00000378084

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

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

Mar 30, 2024

The c.338G>A (p.S113N) alteration is located in exon 5 (coding exon 5) of the ZNF326 gene. This alteration results from a G to A substitution at nucleotide position 338, causing the serine (S) at amino acid position 113 to be replaced by an asparagine (N). 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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.068
Sift	Benign	0.32	T
Sift4G	Benign	0.66	T
Polyphen		0.0050	B
Vest4		0.25
MutPred		0.17		Loss of phosphorylation at S113 (P = 0.0036);
MVP		0.043
MPC		0.27
ClinPred		0.22	T
GERP RS		4.8
Varity_R		0.051
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1311638851; hg19: chr1-90473032;