rs2664537

chr20-41185089-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000544979.6(ZHX3):c.2747C>T(p.Pro916Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,562,680 control chromosomes in the GnomAD database, including 20,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1709 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18705 hom.)
• Consequence: ZHX3 ENST00000544979.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.06

Genes affected

ZHX3 (HGNC:15935): (zinc fingers and homeoboxes 3) This gene encodes a member of the zinc fingers and homeoboxes (ZHX) gene family. The encoded protein contains two C2H2-type zinc fingers and five homeodomains and forms a dimer with itself or with zinc fingers and homeoboxes family member 1. In the nucleus, the dimerized protein interacts with the A subunit of the ubiquitous transcription factor nuclear factor-Y and may function as a transcriptional repressor. [provided by RefSeq, Jul 2008]

PLCG1 (HGNC:9065): (phospholipase C gamma 1) The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of receptor-mediated tyrosine kinase activators. For example, when activated by SRC, the encoded protein causes the Ras guanine nucleotide exchange factor RasGRP1 to translocate to the Golgi, where it activates Ras. Also, this protein has been shown to be a major substrate for heparin-binding growth factor 1 (acidic fibroblast growth factor)-activated tyrosine kinase. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042850673).
• BP6: Variant 20-41185089-G-A is Benign according to our data. Variant chr20-41185089-G-A is described in ClinVar as [Benign]. Clinvar id is 1266725.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZHX3	NM_001384317.1	c.*102C>T		3_prime_UTR_variant	4/4	ENST00000683867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZHX3	ENST00000683867.1	c.*102C>T		3_prime_UTR_variant	4/4		NM_001384317.1	P1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21170 AN: 152044 Hom.: 1709 Cov.: 33

Gnomad AFR AF: 0.0958

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.135 AC: 23557 AN: 174830 Hom.: 1909 AF XY: 0.130 AC XY: 12037 AN XY: 92476

Gnomad AFR exome AF: 0.0929

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00355

Gnomad SAS exome AF: 0.0441

Gnomad FIN exome AF: 0.253

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.156 AC: 220688 AN: 1410518 Hom.: 18705 Cov.: 32 AF XY: 0.154 AC XY: 107042 AN XY: 696664

Gnomad4 AFR exome AF: 0.0936

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.00622

Gnomad4 SAS exome AF: 0.0436

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.139 AC: 21180 AN: 152162 Hom.: 1709 Cov.: 33 AF XY: 0.139 AC XY: 10363 AN XY: 74408

Gnomad4 AFR AF: 0.0958

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.139

Alfa AF: 0.158 Hom.: 2730

Bravo AF: 0.129

TwinsUK AF: 0.160 AC: 594

ALSPAC AF: 0.166 AC: 641

ExAC AF: 0.101 AC: 11802

Asia WGS AF: 0.0330 AC: 116 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.54
Dann	Benign	0.70
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.031	N
MetaRNN	Benign	0.0043	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
Sift4G	Benign	0.088	T;D;D;T
Vest4		0.051
ClinPred		0.0052	T
GERP RS		-9.5

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: rs2664537; hg19: chr20-39813729; COSMIC: COSV58380407; COSMIC: COSV58380407;