NM_001101.5:c.930_*52del

Variant names:

• chr7-5527695-CGCAAGTTAGGTTTTGTCAAGAAAGGGTGTAACGCAACTAAGTCATAGTCCGCCTAGAAGCATTTGCGGTGGACGATGGAGGGGCCGGACTCGTCATACTCCTGCTTGCTGATCCACATCTGCTGGAAGGTGGACAGCGAGGCCAGGATGGAGCCGCCGATCCACACGGAGTACTTGCGCTCAGGAGGAGCAATGATCTGAGGAGGGAAGGGGACAGGCAGTGAGGACCCTGGATGTGACAGCTCCCCACACACCACAGGACCCCACAGCCGACCTGCCCAGGTCAGCTCAGGCAGGAAAGACACCCACCTTGATCTTCATTGTGCTGGGTGCCAGGGCAGTGATCTCCTTCTGCATCCTGTCG-C
• NM_001101.5:c.930_*52del

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001101.5(ACTB):​c.930_*52del​(p.Ala310fs) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 frameshift, stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.68
• Publications: 0 publications found

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]

ACTB Gene-Disease associations (from GenCC):

• Baraitser-Winter cerebrofrontofacial syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Baraitser-Winter syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• developmental malformations-deafness-dystonia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, Genomics England PanelApp
• ACTB-associated syndromic thrombocytopenia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• 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 VariationId is 987424.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101.5. 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
	ACTB	NM_001101.5	MANE Select	c.930_*52del	p.Ala310fs	frameshift stop_lost	Exon 6 of 6	NP_001092.1	P60709

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTB	ENST00000646664.1	MANE Select	c.930_*52del	p.Ala310fs	frameshift stop_lost	Exon 5 of 6	ENSP00000494750.1	P60709
	ACTB	ENST00000425660.5	TSL:1	n.*593_*843del		conservative_inframe_deletion	Exon 7 of 7	ENSP00000409264.1	G5E9R0
	ACTB	ENST00000899428.1		c.364-13_*52del		exon_loss	Exon 4 of 5	ENSP00000569487.1

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

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

Other links and lift over

hg19: chr7-5567326;