19-34741160-C-T

Variant names:

• chr19-34741160-C-T
• NM_001029997.4:c.779C>T

Variant summary

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

The NM_001029997.4(ZNF181):​c.779C>T​(p.Thr260Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF181 NM_001029997.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45
• Publications: 0 publications found

Genes affected

ZNF181 (HGNC:12971): (zinc finger protein 181) Zinc finger proteins have been shown to interact with nucleic acids and to have diverse functions. The zinc finger domain is a conserved amino acid sequence motif containing 2 specifically positioned cysteines and 2 histidines that are involved in coordinating zinc. Kruppel-related proteins form 1 family of zinc finger proteins. See MIM 604749 for additional information on zinc finger proteins.[supplied by OMIM, Jul 2003]

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=0.39191234).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029997.4. 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
	ZNF181	NM_001029997.4	MANE Select	c.779C>T	p.Thr260Ile	missense	Exon 4 of 4	NP_001025168.2	Q2M3W8-1
	ZNF181	NM_001145665.2		c.776C>T	p.Thr259Ile	missense	Exon 4 of 4	NP_001139137.1	Q2M3W8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF181	ENST00000492450.3	TSL:1 MANE Select	c.779C>T	p.Thr260Ile	missense	Exon 4 of 4	ENSP00000420727.1	Q2M3W8-1
	ZNF181	ENST00000459757.6	TSL:1	c.776C>T	p.Thr259Ile	missense	Exon 4 of 4	ENSP00000419435.1	Q2M3W8-3
	ZNF181	ENST00000392232.7	TSL:5	c.911C>T	p.Thr304Ile	missense	Exon 6 of 6	ENSP00000376065.3	F8W889

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727194

⚠️ 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: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.15
Sift	Benign	0.031	D
Sift4G	Uncertain	0.028	D
Polyphen		0.99	D
Vest4		0.43
MutPred		0.58		Loss of phosphorylation at T260 (P = 0.0424)
MVP		0.58
MPC		0.85
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.31
gMVP		0.095
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

hg19: chr19-35232065;