chr8-76704140-A-C

Position:

• chr8-76704140-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024721.5(ZFHX4):​c.52A>C​(p.Thr18Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 5.91

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26931345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX4	NM_024721.5	c.52A>C	p.Thr18Pro	missense_variant	2/11	ENST00000651372.2
ZFHX4	NM_001410934.1	c.52A>C	p.Thr18Pro	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX4	ENST00000651372.2	c.52A>C	p.Thr18Pro	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

Feb 16, 2023

The c.52A>C (p.T18P) alteration is located in exon 2 (coding exon 1) of the ZFHX4 gene. This alteration results from a A to C substitution at nucleotide position 52, causing the threonine (T) at amino acid position 18 to be replaced by a proline (P). 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	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	.;.;.;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;.;T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N;D;D;D;D;N
REVEL	Benign	0.24
Sift	Benign	0.039	D;D;D;D;D;D
Sift4G	Benign	0.091	T;D;D;D;D;T
Vest4		0.58
MutPred		0.070		Loss of phosphorylation at T18 (P = 0.0484);Loss of phosphorylation at T18 (P = 0.0484);Loss of phosphorylation at T18 (P = 0.0484);Loss of phosphorylation at T18 (P = 0.0484);Loss of phosphorylation at T18 (P = 0.0484);Loss of phosphorylation at T18 (P = 0.0484);
MVP		0.21
MPC		0.57
ClinPred		0.93	D
GERP RS		5.5
gMVP		0.10

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: chr8-77616375;