14-23522070-G-A

Variant names:

• chr14-23522070-G-A
• rs750729691
• NM_033400.3:c.7611C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_033400.3(ZFHX2):​c.7611C>T​(p.Ala2537Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,536,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: ZFHX2 NM_033400.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0180

Genes affected

ZFHX2 (HGNC:20152): (zinc finger homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in regulation of sensory perception of pain. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZFHX2-AS1 (HGNC:52658): (ZFHX2 antisense RNA 1)

THTPA (HGNC:18987): (thiamine triphosphatase) This gene encodes an enzyme which catalyzes the biosynthesis of thiamine disphophate (vitamin B1) by hydrolysis of thiamine triphosphate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-23522070-G-A is Benign according to our data. Variant chr14-23522070-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3771335.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.018 with no splicing effect.
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX2	NM_033400.3	c.7611C>T	p.Ala2537Ala	synonymous_variant	Exon 10 of 10	ENST00000419474.5	NP_207646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX2	ENST00000419474.5	c.7611C>T	p.Ala2537Ala	synonymous_variant	Exon 10 of 10	5	NM_033400.3	ENSP00000413418.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000133 AC: 18 AN: 135002 Hom.: 0 AF XY: 0.000109 AC XY: 8 AN XY: 73452

Gnomad AFR exome AF: 0.000464

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000226

Gnomad OTH exome AF: 0.000241

GnomAD4 exome AF: 0.000220 AC: 304 AN: 1383970 Hom.: 1 Cov.: 36 AF XY: 0.000209 AC XY: 143 AN XY: 682930

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.0000841

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000224

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.000294

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74376

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000117

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ZFHX2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.8
DANN	Benign	0.88

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: rs750729691; hg19: chr14-23991279;