19-34741141-C-T

Variant names:

• chr19-34741141-C-T
• rs762403551
• NM_001029997.4:c.760C>T

Variant summary

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

The NM_001029997.4(ZNF181):​c.760C>T​(p.Arg254Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,614,026 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R254L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: ZNF181 NM_001029997.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.72

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

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=0.15927693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF181	NM_001029997.4	c.760C>T	p.Arg254Cys	missense_variant	Exon 4 of 4	ENST00000492450.3	NP_001025168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF181	ENST00000492450.3	c.760C>T	p.Arg254Cys	missense_variant	Exon 4 of 4	1	NM_001029997.4	ENSP00000420727.1
ZNF181	ENST00000459757.6	c.757C>T	p.Arg253Cys	missense_variant	Exon 4 of 4	1		ENSP00000419435.1
ZNF181	ENST00000392232.7	c.892C>T	p.Arg298Cys	missense_variant	Exon 6 of 6	5		ENSP00000376065.3
ZNF181	ENST00000448715.2	n.1858C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000439 AC: 11 AN: 250348 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135704

Gnomad AFR exome AF: 0.0000641

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461798 Hom.: 0 Cov.: 34 AF XY: 0.0000413 AC XY: 30 AN XY: 727198

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

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: 0.0000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74368

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.760C>T (p.R254C) alteration is located in exon 4 (coding exon 4) of the ZNF181 gene. This alteration results from a C to T substitution at nucleotide position 760, causing the arginine (R) at amino acid position 254 to be replaced by a cysteine (C). 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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	.;.;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.060	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.40
MVP		0.45
MPC		0.89
ClinPred		0.54	D
GERP RS		1.8
Varity_R		0.21
gMVP		0.077

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: rs762403551; hg19: chr19-35232046;