NM_003461.5:c.298A>C

Variant names:

• chr7-143382337-A-C
• NM_003461.5:c.298A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003461.5(ZYX):​c.298A>C​(p.Ile100Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZYX NM_003461.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.736
• Publications: 0 publications found

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]

FAM131B-AS2 (HGNC:56141): (FAM131B antisense RNA 2)

FAM131B (HGNC:22202): (family with sequence similarity 131 member B) Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052648723).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003461.5. 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
	ZYX	NM_003461.5	MANE Select	c.298A>C	p.Ile100Leu	missense	Exon 3 of 10	NP_003452.1	Q15942-1
	ZYX	NM_001010972.2		c.298A>C	p.Ile100Leu	missense	Exon 3 of 10	NP_001010972.1	Q15942-1
	ZYX	NM_001362783.2		c.298A>C	p.Ile100Leu	missense	Exon 3 of 9	NP_001349712.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZYX	ENST00000322764.10	TSL:1 MANE Select	c.298A>C	p.Ile100Leu	missense	Exon 3 of 10	ENSP00000324422.5	Q15942-1
	ZYX	ENST00000943399.1		c.298A>C	p.Ile100Leu	missense	Exon 3 of 11	ENSP00000613458.1
	ZYX	ENST00000869086.1		c.298A>C	p.Ile100Leu	missense	Exon 3 of 10	ENSP00000539145.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.74
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	0.73	T
Polyphen		0.012	B
Vest4		0.32
MutPred		0.27		Gain of glycosylation at P105 (P = 0.1435)
MVP		0.34
MPC		0.10
ClinPred		0.084	T
GERP RS		0.81
PromoterAI		0.036	Neutral
Varity_R		0.11
gMVP		0.11
Mutation Taster		=94/6	polymorphism

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

hg19: chr7-143079430;