NM_003461.5:c.1637T>G

Variant names:

• chr7-143390600-T-G
• NM_003461.5:c.1637T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003461.5(ZYX):​c.1637T>G​(p.Ile546Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZYX NM_003461.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28434753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZYX	NM_003461.5	c.1637T>G	p.Ile546Ser	missense_variant	Exon 10 of 10	ENST00000322764.10	NP_003452.1
ZYX	NM_001010972.2	c.1637T>G	p.Ile546Ser	missense_variant	Exon 10 of 10		NP_001010972.1
ZYX	NM_001362783.2	c.1544T>G	p.Ile515Ser	missense_variant	Exon 9 of 9		NP_001349712.1
ZYX	XM_047420817.1	c.1544T>G	p.Ile515Ser	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.1637T>G	p.Ile546Ser	missense_variant	Exon 10 of 10	1	NM_003461.5	ENSP00000324422.5
ZYX	ENST00000354434.8	c.1541T>G	p.Ile514Ser	missense_variant	Exon 8 of 8	2		ENSP00000346417.4
ZYX	ENST00000392910.6	c.1166T>G	p.Ile389Ser	missense_variant	Exon 9 of 9	2		ENSP00000376642.2
EPHA1	ENST00000458129.1	n.340A>C		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1425068 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 705082

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1637T>G (p.I546S) alteration is located in exon 10 (coding exon 9) of the ZYX gene. This alteration results from a T to G substitution at nucleotide position 1637, causing the isoleucine (I) at amino acid position 546 to be replaced by a serine (S). 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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	-0.32	N;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Uncertain	0.47
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.43
MutPred		0.40		Gain of disorder (P = 0.0018);.;.;
MVP		0.93
MPC		0.51
ClinPred		0.97	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.080
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-143087693;