rs373186650

Variant names:

• chr19-21143563-T-C
• rs373186650
• NM_133473.4:c.16T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_133473.4(ZNF431):​c.16T>C​(p.Tyr6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ZNF431 NM_133473.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.279
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025286674).

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.16T>C	p.Tyr6His	missense	Exon 2 of 5	NP_597730.2	Q8TF32
	ZNF431	NM_001319124.2		c.16T>C	p.Tyr6His	missense	Exon 2 of 5	NP_001306053.1
	ZNF431	NM_001319126.2		c.-280T>C		5_prime_UTR	Exon 2 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.16T>C	p.Tyr6His	missense	Exon 2 of 5	ENSP00000308578.6	Q8TF32
	ZNF431	ENST00000949855.1		c.16T>C	p.Tyr6His	missense	Exon 2 of 6	ENSP00000619914.1
	ZNF431	ENST00000949854.1		c.16T>C	p.Tyr6His	missense	Exon 2 of 6	ENSP00000619913.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251428 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461372 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727044

African (AFR) AF: 0.000657 AC: 22 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111566

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74462

African (AFR) AF: 0.000529 AC: 22 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

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	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.28
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.0050
Sift	Benign	0.069	T
Sift4G	Benign	0.51	T
Polyphen		0.38	B
Vest4		0.15
MVP		0.17
MPC		0.14
ClinPred		0.013	T
GERP RS		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.15
Mutation Taster		=98/2	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: rs373186650; hg19: chr19-21326366;