7-5527695-CGCAAGTTAGGTTTTGTCAAGAAAGGGTGTAACGCAACTAAGTCATAGTCCGCCTAGAAGCATTTGCGGTGGACGATGGAGGGGCCGGACTCGTCATACTCCTGCTTGCTGATCCACATCTGCTGGAAGGTGGACAGCGAGGCCAGGATGGAGCCGCCGATCCACACGGAGTACTTGCGCTCAGGAGGAGCAATGATCTGAGGAGGGAAGGGGACAGGCAGTGAGGACCCTGGATGTGACAGCTCCCCACACACCACAGGACCCCACAGCCGACCTGCCCAGGTCAGCTCAGGCAGGAAAGACACCCACCTTGATCTTCATTGTGCTGGGTGCCAGGGCAGTGATCTCCTTCTGCATCCTGTCG-C

Position:

• chr7-5527695-CGCAAGTTAGGTTTTGTCAAGAAAGGGTGTAACGCAACTAAGTCATAGTCCGCCTAGAAGCATTTGCGGTGGACGATGGAGGGGCCGGACTCGTCATACTCCTGCTTGCTGATCCACATCTGCTGGAAGGTGGACAGCGAGGCCAGGATGGAGCCGCCGATCCACACGGAGTACTTGCGCTCAGGAGGAGCAATGATCTGAGGAGGGAAGGGGACAGGCAGTGAGGACCCTGGATGTGACAGCTCCCCACACACCACAGGACCCCACAGCCGACCTGCCCAGGTCAGCTCAGGCAGGAAAGACACCCACCTTGATCTTCATTGTGCTGGGTGCCAGGGCAGTGATCTCCTTCTGCATCCTGTCG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001101.5(ACTB):​c.930_*52del variant causes a splice acceptor, splice donor, stop lost, splice donor 5th base, 3 prime UTR, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A310A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTB NM_001101.5 splice_acceptor, splice_donor, stop_lost, splice_donor_5th_base, 3_prime_UTR, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.68

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.65868795 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-5527695-CGCAAGTTAGGTTTTGTCAAGAAAGGGTGTAACGCAACTAAGTCATAGTCCGCCTAGAAGCATTTGCGGTGGACGATGGAGGGGCCGGACTCGTCATACTCCTGCTTGCTGATCCACATCTGCTGGAAGGTGGACAGCGAGGCCAGGATGGAGCCGCCGATCCACACGGAGTACTTGCGCTCAGGAGGAGCAATGATCTGAGGAGGGAAGGGGACAGGCAGTGAGGACCCTGGATGTGACAGCTCCCCACACACCACAGGACCCCACAGCCGACCTGCCCAGGTCAGCTCAGGCAGGAAAGACACCCACCTTGATCTTCATTGTGCTGGGTGCCAGGGCAGTGATCTCCTTCTGCATCCTGTCG-C is Pathogenic according to our data. Variant chr7-5527695-CGCAAGTTAGGTTTTGTCAAGAAAGGGTGTAACGCAACTAAGTCATAGTCCGCCTAGAAGCATTTGCGGTGGACGATGGAGGGGCCGGACTCGTCATACTCCTGCTTGCTGATCCACATCTGCTGGAAGGTGGACAGCGAGGCCAGGATGGAGCCGCCGATCCACACGGAGTACTTGCGCTCAGGAGGAGCAATGATCTGAGGAGGGAAGGGGACAGGCAGTGAGGACCCTGGATGTGACAGCTCCCCACACACCACAGGACCCCACAGCCGACCTGCCCAGGTCAGCTCAGGCAGGAAAGACACCCACCTTGATCTTCATTGTGCTGGGTGCCAGGGCAGTGATCTCCTTCTGCATCCTGTCG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 987424.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTB	NM_001101.5	c.930_*52del		splice_acceptor_variant, splice_donor_variant, stop_lost, splice_donor_5th_base_variant, 3_prime_UTR_variant, intron_variant	5/6	ENST00000646664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTB	ENST00000646664.1	c.930_*52del		splice_acceptor_variant, splice_donor_variant, stop_lost, splice_donor_5th_base_variant, 3_prime_UTR_variant, intron_variant	5/6		NM_001101.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-5567326;