3-126459671-C-T

Variant names:

• chr3-126459671-C-T
• rs773536066
• NM_025112.5:c.2194G>A

Variant summary

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

The NM_025112.5(ZXDC):​c.2194G>A​(p.Gly732Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZXDC NM_025112.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

Genes affected

ZXDC (HGNC:28160): (ZXD family zinc finger C) Enables C2H2 zinc finger domain binding activity; LRR domain binding activity; and transcription coactivator activity. Involved in positive regulation of transcription, DNA-templated. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZXDC	NM_025112.5	c.2194G>A	p.Gly732Arg	missense_variant	Exon 7 of 10	ENST00000389709.8	NP_079388.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZXDC	ENST00000389709.8	c.2194G>A	p.Gly732Arg	missense_variant	Exon 7 of 10	1	NM_025112.5	ENSP00000374359.3
ZXDC	ENST00000515545.5	n.*259+1599G>A		intron_variant	Intron 6 of 8	1		ENSP00000426532.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2194G>A (p.G732R) alteration is located in exon 7 (coding exon 7) of the ZXDC gene. This alteration results from a G to A substitution at nucleotide position 2194, causing the glycine (G) at amino acid position 732 to be replaced by an arginine (R). 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
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.20		Gain of methylation at K729 (P = 0.051);
MVP		0.43
MPC		0.23
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.64
gMVP		0.23

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: rs773536066; hg19: chr3-126178514;