chr7-143381759-T-C

Variant names:

• chr7-143381759-T-C
• rs201850974
• NM_003461.5:c.188T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003461.5(ZYX):​c.188T>C​(p.Ile63Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,429,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I63S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ZYX NM_003461.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.50
• 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 (HGNC:22202): (family with sequence similarity 131 member B) Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25536013).

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.188T>C	p.Ile63Thr	missense	Exon 2 of 10	NP_003452.1	Q15942-1
	ZYX	NM_001010972.2		c.188T>C	p.Ile63Thr	missense	Exon 2 of 10	NP_001010972.1	Q15942-1
	ZYX	NM_001362783.2		c.188T>C	p.Ile63Thr	missense	Exon 2 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.188T>C	p.Ile63Thr	missense	Exon 2 of 10	ENSP00000324422.5	Q15942-1
	ZYX	ENST00000943399.1		c.188T>C	p.Ile63Thr	missense	Exon 2 of 11	ENSP00000613458.1
	ZYX	ENST00000869086.1		c.188T>C	p.Ile63Thr	missense	Exon 2 of 10	ENSP00000539145.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429050 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708078

African (AFR) AF: 0.00 AC: 0 AN: 31888

American (AMR) AF: 0.00 AC: 0 AN: 41460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 37124

South Asian (SAS) AF: 0.00 AC: 0 AN: 83060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1095968

Other (OTH) AF: 0.00 AC: 0 AN: 58802

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.21	T
Polyphen		0.42	B
Vest4		0.32
MutPred		0.25		Gain of phosphorylation at I63 (P = 0.0022)
MVP		0.64
MPC		0.13
ClinPred		0.51	D
GERP RS		4.0
PromoterAI		0.027	Neutral
Varity_R		0.14
gMVP		0.14
Mutation Taster		=77/23	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

dbSNP: rs201850974; hg19: chr7-143078852;