chr1-89998110-A-G

Variant names:

• chr1-89998110-A-G
• rs201232871
• NM_182976.4:c.17A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_182976.4(ZNF326):​c.17A>G​(p.Asp6Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF326 NM_182976.4 missense, splice_region
• Scores: Splicing: ADA: 0.5809
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4033016).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182976.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF326	NM_182976.4	MANE Select	c.17A>G	p.Asp6Gly	missense splice_region	Exon 2 of 12	NP_892021.1	Q5BKZ1-1
	ZNF326	NM_001320185.2		c.17A>G	p.Asp6Gly	missense splice_region	Exon 2 of 12	NP_001307114.1	A0A0A0MRN4
	ZNF326	NM_181781.4		c.-138A>G		splice_region	Exon 2 of 10	NP_861446.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF326	ENST00000340281.9	TSL:1 MANE Select	c.17A>G	p.Asp6Gly	missense splice_region	Exon 2 of 12	ENSP00000340796.4	Q5BKZ1-1
	ZNF326	ENST00000370447.3	TSL:1	c.17A>G	p.Asp6Gly	missense splice_region	Exon 2 of 12	ENSP00000359476.2	A0A0A0MRN4
	ZNF326	ENST00000361911.9	TSL:1	c.17A>G	p.Asp6Gly	missense splice_region	Exon 2 of 4	ENSP00000355318.5	Q5BKZ1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460514 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726544

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111654

Other (OTH) AF: 0.00 AC: 0 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0054
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.16
Sift	Uncertain	0.014	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.49	P
Vest4		0.67
MutPred		0.13		Loss of stability (P = 0.0983)
MVP		0.23
MPC		0.40
ClinPred		0.72	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.27
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.58
dbscSNV1_RF	Benign	0.52
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

Other links and lift over

dbSNP: rs201232871; hg19: chr1-90463669;