19-21167571-G-T

Variant names:

• chr19-21167571-G-T
• rs751106970
• NM_133473.4:c.224G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001319126.2(ZNF431):​c.-72G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000426 in 1,407,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: ZNF431 NM_001319126.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.3771
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.523
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.744

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319126.2. 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.224G>T	p.Gly75Val	missense splice_region	Exon 4 of 5	NP_597730.2	Q8TF32
	ZNF431	NM_001319126.2		c.-72G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 6	NP_001306055.1
	ZNF431	NM_001319127.2		c.-178G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 6	NP_001306056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF431	ENST00000311048.11	TSL:1 MANE Select	c.224G>T	p.Gly75Val	missense splice_region	Exon 4 of 5	ENSP00000308578.6	Q8TF32
	ZNF431	ENST00000949855.1		c.347G>T	p.Gly116Val	missense	Exon 5 of 6	ENSP00000619914.1
	ZNF431	ENST00000949854.1		c.275G>T	p.Gly92Val	missense	Exon 5 of 6	ENSP00000619913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000875 AC: 2 AN: 228462 AF XY: 0.00000803

Gnomad AFR exome AF: 0.00

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: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000426 AC: 6 AN: 1407742 Hom.: 0 Cov.: 29 AF XY: 0.00000714 AC XY: 5 AN XY: 700362

African (AFR) AF: 0.00 AC: 0 AN: 30966

American (AMR) AF: 0.00 AC: 0 AN: 36392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38294

South Asian (SAS) AF: 0.00 AC: 0 AN: 80220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 0.00000552 AC: 6 AN: 1086708

Other (OTH) AF: 0.00 AC: 0 AN: 57400

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0018	T
MetaRNN	Pathogenic	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.52
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.043
Sift	Uncertain	0.018	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.81		Loss of relative solvent accessibility (P = 0.0793)
MVP		0.14
MPC		0.54
ClinPred		0.50	D
GERP RS		-0.84
Varity_R		0.30
gMVP		0.37
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.54		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751106970; hg19: chr19-21350374;