rs13447394

chr7-5529667-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001101.5(ACTB):c.-6-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 1,610,772 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (23 hom.)
• Consequence: ACTB NM_001101.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008179
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.101

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=-0.77).
• BP6: Variant 7-5529667-C-A is Benign according to our data. Variant chr7-5529667-C-A is described in ClinVar as [Benign]. Clinvar id is 195111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529667-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00318 (484/152302) while in subpopulation NFE AF= 0.00568 (386/67992). AF 95% confidence interval is 0.00521. There are 1 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 484 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTB	NM_001101.5	c.-6-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000646664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTB	ENST00000646664.1	c.-6-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001101.5	P1

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 484 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00771

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00568

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00303 AC: 737 AN: 243158 Hom.: 4 AF XY: 0.00302 AC XY: 403 AN XY: 133468

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000843

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00270

Gnomad NFE exome AF: 0.00531

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00479 AC: 6985 AN: 1458470 Hom.: 23 Cov.: 32 AF XY: 0.00466 AC XY: 3382 AN XY: 725636

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.00289

Gnomad4 NFE exome AF: 0.00581

Gnomad4 OTH exome AF: 0.00327

GnomAD4 genome AF: 0.00318 AC: 484 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74484

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00568

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00447 Hom.: 1

Bravo AF: 0.00319

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00468

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 17, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ACTB: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2016	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. -

Baraitser-Winter syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Developmental malformations-deafness-dystonia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	6.6
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.060
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

LitVar

Other links and lift over

dbSNP: rs13447394; hg19: chr7-5569298;