rs187363412

Variant names:

• chr19-21182743-G-C
• rs187363412
• NM_133473.4:c.440G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-21182743-G-C
• chr19-21182743-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133473.4(ZNF431):​c.440G>C​(p.Gly147Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G147V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF431 NM_133473.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11553708).

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.440G>C	p.Gly147Ala	missense	Exon 5 of 5	NP_597730.2	Q8TF32
	ZNF431	NM_001319124.2		c.443G>C	p.Gly148Ala	missense	Exon 5 of 5	NP_001306053.1
	ZNF431	NM_001319126.2		c.167G>C	p.Gly56Ala	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.440G>C	p.Gly147Ala	missense	Exon 5 of 5	ENSP00000308578.6	Q8TF32
	ZNF431	ENST00000949855.1		c.563G>C	p.Gly188Ala	missense	Exon 6 of 6	ENSP00000619914.1
	ZNF431	ENST00000949854.1		c.491G>C	p.Gly164Ala	missense	Exon 6 of 6	ENSP00000619913.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461620 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33470

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.4
DANN	Benign	0.67
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.061
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.042
Sift	Uncertain	0.010	D
Sift4G	Benign	0.20	T
Polyphen		0.21	B
Vest4		0.085
MutPred		0.19		Gain of ubiquitination at K146 (P = 0.0817)
MVP		0.076
MPC		0.36
ClinPred		0.52	D
GERP RS		-0.76
Varity_R		0.15
gMVP		0.011
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs187363412; hg19: chr19-21365546;