7-143390632-G-T

Variant names:

• chr7-143390632-G-T
• rs952111937
• NM_003461.5:c.1669G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_003461.5(ZYX):​c.1669G>T​(p.Asp557Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000557 in 1,435,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: ZYX NM_003461.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75

Genes affected

ZYX (HGNC:13200): (zyxin) Focal adhesions are actin-rich structures that enable cells to adhere to the extracellular matrix and at which protein complexes involved in signal transduction assemble. Zyxin is a zinc-binding phosphoprotein that concentrates at focal adhesions and along the actin cytoskeleton. Zyxin has an N-terminal proline-rich domain and three LIM domains in its C-terminal half. The proline-rich domain may interact with SH3 domains of proteins involved in signal transduction pathways while the LIM domains are likely involved in protein-protein binding. Zyxin may function as a messenger in the signal transduction pathway that mediates adhesion-stimulated changes in gene expression and may modulate the cytoskeletal organization of actin bundles. Alternative splicing results in multiple transcript variants that encode the same isoform. [provided by RefSeq, Jul 2008]

EPHA1 (HGNC:3385): (EPH receptor A1) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene is expressed in some human cancer cell lines and has been implicated in carcinogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZYX	NM_003461.5	c.1669G>T	p.Asp557Tyr	missense_variant	Exon 10 of 10	ENST00000322764.10	NP_003452.1
ZYX	NM_001010972.2	c.1669G>T	p.Asp557Tyr	missense_variant	Exon 10 of 10		NP_001010972.1
ZYX	NM_001362783.2	c.1576G>T	p.Asp526Tyr	missense_variant	Exon 9 of 9		NP_001349712.1
ZYX	XM_047420817.1	c.1576G>T	p.Asp526Tyr	missense_variant	Exon 9 of 9		XP_047276773.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZYX	ENST00000322764.10	c.1669G>T	p.Asp557Tyr	missense_variant	Exon 10 of 10	1	NM_003461.5	ENSP00000324422.5
ZYX	ENST00000354434.8	c.1573G>T	p.Asp525Tyr	missense_variant	Exon 8 of 8	2		ENSP00000346417.4
ZYX	ENST00000392910.6	c.1198G>T	p.Asp400Tyr	missense_variant	Exon 9 of 9	2		ENSP00000376642.2
EPHA1	ENST00000458129.1	n.308C>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000476 AC: 1 AN: 210132 Hom.: 0 AF XY: 0.00000891 AC XY: 1 AN XY: 112270

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000388

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000557 AC: 8 AN: 1435740 Hom.: 0 Cov.: 30 AF XY: 0.00000843 AC XY: 6 AN XY: 711448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000977

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.3	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.56
MutPred		0.58		Loss of solvent accessibility (P = 0.0152);.;.;
MVP		0.96
MPC		0.57
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.85
gMVP		0.78

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: rs952111937; hg19: chr7-143087725;