8-76704110-C-A

Position:

• chr8-76704110-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024721.5(ZFHX4):​c.22C>A​(p.Pro8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFHX4 NM_024721.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

Genes affected

ZFHX4 (HGNC:30939): (zinc finger homeobox 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087427974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX4	NM_024721.5	c.22C>A	p.Pro8Thr	missense_variant	2/11	ENST00000651372.2
ZFHX4	NM_001410934.1	c.22C>A	p.Pro8Thr	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX4	ENST00000651372.2	c.22C>A	p.Pro8Thr	missense_variant	2/11		NM_024721.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.22C>A (p.P8T) alteration is located in exon 2 (coding exon 1) of the ZFHX4 gene. This alteration results from a C to A substitution at nucleotide position 22, causing the proline (P) at amino acid position 8 to be replaced by a threonine (T). 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
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.058	.;.;.;.;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T;.;T;T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.087	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;.;.;.;.
MutationTaster	Benign	0.73	N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.38	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.70	T;T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T
Vest4		0.16
MutPred		0.064		Gain of phosphorylation at P8 (P = 0.0168);Gain of phosphorylation at P8 (P = 0.0168);Gain of phosphorylation at P8 (P = 0.0168);Gain of phosphorylation at P8 (P = 0.0168);Gain of phosphorylation at P8 (P = 0.0168);Gain of phosphorylation at P8 (P = 0.0168);
MVP		0.043
MPC		0.58
ClinPred		0.62	D
GERP RS		4.6
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs778983175; hg19: chr8-77616345;