7-143381759-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003461.5(ZYX):​c.188T>G​(p.Ile63Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00195 in 1,581,214 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (14 hom.)
• Consequence: ZYX NM_003461.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.50
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044882298).
• BP6: Variant 7-143381759-T-G is Benign according to our data. Variant chr7-143381759-T-G is described in ClinVar as Benign. ClinVar VariationId is 784501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00741 (1127/152170) while in subpopulation AFR AF = 0.0224 (931/41558). AF 95% confidence interval is 0.0212. There are 13 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1127 AD gene.

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>G	p.Ile63Ser	missense	Exon 2 of 10	NP_003452.1	Q15942-1
	ZYX	NM_001010972.2		c.188T>G	p.Ile63Ser	missense	Exon 2 of 10	NP_001010972.1	Q15942-1
	ZYX	NM_001362783.2		c.188T>G	p.Ile63Ser	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>G	p.Ile63Ser	missense	Exon 2 of 10	ENSP00000324422.5	Q15942-1
	ZYX	ENST00000943399.1		c.188T>G	p.Ile63Ser	missense	Exon 2 of 11	ENSP00000613458.1
	ZYX	ENST00000869086.1		c.188T>G	p.Ile63Ser	missense	Exon 2 of 10	ENSP00000539145.1

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1124 AN: 152052 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00647

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00240 AC: 457 AN: 190776 AF XY: 0.00194

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.00488

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000963

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00137 AC: 1955 AN: 1429044 Hom.: 14 Cov.: 31 AF XY: 0.00129 AC XY: 915 AN XY: 708076

African (AFR) AF: 0.0206 AC: 657 AN: 31888

American (AMR) AF: 0.00429 AC: 178 AN: 41454

Ashkenazi Jewish (ASJ) AF: 0.00499 AC: 127 AN: 25440

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37124

South Asian (SAS) AF: 0.0000482 AC: 4 AN: 83060

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

Middle Eastern (MID) AF: 0.00708 AC: 40 AN: 5646

European-Non Finnish (NFE) AF: 0.000688 AC: 754 AN: 1095968

Other (OTH) AF: 0.00330 AC: 194 AN: 58802

GnomAD4 genome AF: 0.00741 AC: 1127 AN: 152170 Hom.: 13 Cov.: 33 AF XY: 0.00737 AC XY: 548 AN XY: 74406

African (AFR) AF: 0.0224 AC: 931 AN: 41558

American (AMR) AF: 0.00640 AC: 98 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 67952

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00277 Hom.: 1

Bravo AF: 0.00846

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0144 AC: 51

ESP6500EA AF: 0.00107 AC: 8

ExAC AF: 0.00215 AC: 244

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.015
Eigen_PC	Benign	-0.0028
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.21	T
Polyphen		0.84	P
Vest4		0.36
MVP		0.75
MPC		0.15
ClinPred		0.024	T
GERP RS		4.0
PromoterAI		0.0092	Neutral
Varity_R		0.30
gMVP		0.32
Mutation Taster		=87/13	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;