19-21183231-C-T

Variant names:

• chr19-21183231-C-T
• NM_133473.4:c.928C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133473.4(ZNF431):​c.928C>T​(p.His310Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF431 NM_133473.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF431	NM_133473.4	c.928C>T	p.His310Tyr	missense_variant	Exon 5 of 5	ENST00000311048.11	NP_597730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF431	ENST00000311048.11	c.928C>T	p.His310Tyr	missense_variant	Exon 5 of 5	1	NM_133473.4	ENSP00000308578.6
ZNF431	ENST00000600692.5	c.*515C>T		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000470668.1
ZNF431	ENST00000594425.5	c.97-6634C>T		intron_variant	Intron 2 of 2	2		ENSP00000469460.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.928C>T (p.H310Y) alteration is located in exon 5 (coding exon 5) of the ZNF431 gene. This alteration results from a C to T substitution at nucleotide position 928, causing the histidine (H) at amino acid position 310 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0098	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.29
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.76		Loss of disorder (P = 0.0337);
MVP		0.67
MPC		0.54
ClinPred		0.98	D
GERP RS		1.0
Varity_R		0.29
gMVP		0.032

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-21366034;