NM_133473.4:c.224G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_133473.4(ZNF431):​c.224G>T​(p.Gly75Val) variant causes a missense, splice region 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_133473.4 missense, splice_region
• Scores: Splicing: ADA: 0.3771
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.523

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF431	NM_133473.4	c.224G>T	p.Gly75Val	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000311048.11	NP_597730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF431	ENST00000311048.11	c.224G>T	p.Gly75Val	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_133473.4	ENSP00000308578.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000875 AC: 2 AN: 228462 Hom.: 0 AF XY: 0.00000803 AC XY: 1 AN XY: 124494

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000552

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.51	T;T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Pathogenic	0.74	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	.;.;M;.
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-7.0	.;.;D;.
REVEL	Benign	0.043
Sift	Uncertain	0.018	.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.35
MutPred		0.81		Loss of relative solvent accessibility (P = 0.0793);Loss of relative solvent accessibility (P = 0.0793);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs751106970; hg19: chr19-21350374;