rs2664537

Variant names:

• chr20-41185089-G-A
• rs2664537
• ENST00000544979.6:c.2747C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384324.1(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. 13/16 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 NM_001384324.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06
• Publications: 25 publications found

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]

PLCG1 Gene-Disease associations (from GenCC):

• immune dysregulation, autoimmunity, and autoinflammation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1266725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384324.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZHX3	NM_001384317.1	MANE Select	c.*102C>T		3_prime_UTR	Exon 4 of 4	NP_001371246.1
	ZHX3	NM_001384324.1		c.2747C>T	p.Pro916Leu	missense	Exon 5 of 5	NP_001371253.1
	ZHX3	NM_001384325.1		c.*162C>T		3_prime_UTR	Exon 5 of 5	NP_001371254.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZHX3	ENST00000544979.6	TSL:1	c.2747C>T	p.Pro916Leu	missense	Exon 5 of 5	ENSP00000443783.2
	ZHX3	ENST00000683867.1	MANE Select	c.*102C>T		3_prime_UTR	Exon 4 of 4	ENSP00000506788.1
	ZHX3	ENST00000559234.5	TSL:1	c.*102C>T		3_prime_UTR	Exon 4 of 4	ENSP00000452965.1

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

GnomAD2 exomes AF: 0.135 AC: 23557 AN: 174830 AF XY: 0.130

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 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

African (AFR) AF: 0.0936 AC: 3035 AN: 32412

American (AMR) AF: 0.133 AC: 4903 AN: 36944

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3721 AN: 25400

East Asian (EAS) AF: 0.00622 AC: 232 AN: 37298

South Asian (SAS) AF: 0.0436 AC: 3514 AN: 80580

European-Finnish (FIN) AF: 0.251 AC: 12524 AN: 49934

Middle Eastern (MID) AF: 0.123 AC: 702 AN: 5712

European-Non Finnish (NFE) AF: 0.170 AC: 184058 AN: 1083742

Other (OTH) AF: 0.137 AC: 7999 AN: 58496

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

African (AFR) AF: 0.0958 AC: 3975 AN: 41502

American (AMR) AF: 0.125 AC: 1905 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 470 AN: 3468

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5180

South Asian (SAS) AF: 0.0408 AC: 197 AN: 4826

European-Finnish (FIN) AF: 0.250 AC: 2651 AN: 10588

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11503 AN: 67994

Other (OTH) AF: 0.139 AC: 292 AN: 2108

Alfa AF: 0.153 Hom.: 3400

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.70
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.96	T
PhyloP100		-1.1
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.0060
Sift	Benign	1.0	T
Sift4G	Benign	0.088	T
Vest4		0.051
ClinPred		0.0052	T
GERP RS		-9.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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