chr19-21183294-C-T

Variant names:

• chr19-21183294-C-T
• rs767798830
• NM_133473.4:c.991C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_133473.4(ZNF431):​c.991C>T​(p.Leu331Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ZNF431 NM_133473.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.389
• Publications: 1 publications found

Genes affected

ZNF431 (HGNC:20809): (zinc finger protein 431) This gene encodes a member of the Krueppel C2H2-type zinc-finger family of proteins. The encoded protein may negatively regulate transcription of target genes, including the hedgehog signaling pathway receptor patched 1, by interacting with histone deacetylases. Mutations in this gene may be associated with non-syndromic facial clefting in human patients. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133473.4. 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
	ZNF431	NM_133473.4	MANE Select	c.991C>T	p.Leu331Phe	missense	Exon 5 of 5	NP_597730.2	Q8TF32
	ZNF431	NM_001319124.2		c.994C>T	p.Leu332Phe	missense	Exon 5 of 5	NP_001306053.1
	ZNF431	NM_001319126.2		c.718C>T	p.Leu240Phe	missense	Exon 6 of 6	NP_001306055.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF431	ENST00000311048.11	TSL:1 MANE Select	c.991C>T	p.Leu331Phe	missense	Exon 5 of 5	ENSP00000308578.6	Q8TF32
	ZNF431	ENST00000949855.1		c.1114C>T	p.Leu372Phe	missense	Exon 6 of 6	ENSP00000619914.1
	ZNF431	ENST00000949854.1		c.1042C>T	p.Leu348Phe	missense	Exon 6 of 6	ENSP00000619913.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000320 AC: 8 AN: 250302 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111920

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152086 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74294

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.000655 AC: 10 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions as Germline

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	Benign	0.30
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0083	T
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.39
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.080
Sift	Benign	0.059	T
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.75		Loss of helix (P = 0.1299)
MVP		0.52
MPC		0.52
ClinPred		0.60	D
GERP RS		1.0
Varity_R		0.11
gMVP		0.026
Mutation Taster		=95/5	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

dbSNP: rs767798830; hg19: chr19-21366097;