rs852423

chr7-5528735-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001101.5(ACTB):c.364-16T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,612,274 control chromosomes in the GnomAD database, including 157,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21479 hom., cov: 33)
  • Exomes 𝑓: 0.43 (136509 hom.)
• Consequence: ACTB NM_001101.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.61

Genes affected

ACTB (HGNC:132): (actin beta) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a major constituent of the contractile apparatus and one of the two nonmuscle cytoskeletal actins that are ubiquitously expressed. Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients. Numerous pseudogenes of this gene have been identified throughout the human genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-5528735-A-G is Benign according to our data. Variant chr7-5528735-A-G is described in ClinVar as [Benign]. Clinvar id is 379378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5528735-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTB	NM_001101.5	c.364-16T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000646664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTB	ENST00000646664.1	c.364-16T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_001101.5	P1

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77230 AN: 151942 Hom.: 21433 Cov.: 33

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.497

GnomAD3 exomes AF: 0.435 AC: 108520 AN: 249490 Hom.: 24897 AF XY: 0.431 AC XY: 58430 AN XY: 135430

Gnomad AFR exome AF: 0.755

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.532

Gnomad EAS exome AF: 0.306

Gnomad SAS exome AF: 0.407

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.427 AC: 623418 AN: 1460214 Hom.: 136509 Cov.: 43 AF XY: 0.426 AC XY: 309661 AN XY: 726516

Gnomad4 AFR exome AF: 0.764

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.531

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.406

Gnomad4 FIN exome AF: 0.444

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.437

GnomAD4 genome AF: 0.509 AC: 77334 AN: 152060 Hom.: 21479 Cov.: 33 AF XY: 0.506 AC XY: 37575 AN XY: 74300

Gnomad4 AFR AF: 0.751

Gnomad4 AMR AF: 0.421

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.391

Gnomad4 FIN AF: 0.435

Gnomad4 NFE AF: 0.417

Gnomad4 OTH AF: 0.497

Alfa AF: 0.422 Hom.: 8366

Bravo AF: 0.519

Asia WGS AF: 0.391 AC: 1359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Baraitser-Winter syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Developmental malformations-deafness-dystonia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.49
Dann	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs852423; hg19: chr7-5568366; COSMIC: COSV59316770; COSMIC: COSV59316770;