rs1554662408

Variant names:

• chr9-26946977-G-GC
• rs1554662408
• NM_001031689.3:c.68dupG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001031689.3(PLAA):​c.68dupG​(p.Leu24ProfsTer55) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLAA NM_001031689.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.63
• Publications: 0 publications found

Genes affected

PLAA (HGNC:9043): (phospholipase A2 activating protein) Predicted to enable ubiquitin binding activity. Involved in cellular response to lipopolysaccharide; macroautophagy; and positive regulation of phospholipase A2 activity. Located in cytoplasm; extracellular exosome; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

IFT74 (HGNC:21424): (intraflagellar transport 74) This gene encodes a core intraflagellar transport (IFT) protein which belongs to a multi-protein complex involved in the transport of ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the cilium as well as inside the cilium, where they assemble into long arrays between the ciliary base and tip. This protein, together with intraflagellar transport protein 81, binds and transports tubulin within cilia and is required for ciliogenesis. Naturally occurring mutations in this gene are associated with amyotrophic lateral sclerosis--frontotemporal dementia and Bardet-Biedl Syndrome. [provided by RefSeq, Mar 2017]

IFT74 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 22

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• spermatogenic failure 58

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-26946977-G-GC is Pathogenic according to our data. Variant chr9-26946977-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 427942.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031689.3. 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
	PLAA	NM_001031689.3	MANE Select	c.68dupG	p.Leu24ProfsTer55	frameshift	Exon 1 of 14	NP_001026859.1	Q9Y263
	PLAA	NM_001321546.2		c.68dupG	p.Leu24ProfsTer55	frameshift	Exon 1 of 13	NP_001308475.1
	IFT74	NM_001099223.3		c.-189_-188insC		upstream_gene	N/A	NP_001092693.1	Q96LB3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAA	ENST00000397292.8	TSL:1 MANE Select	c.68dupG	p.Leu24ProfsTer55	frameshift	Exon 1 of 14	ENSP00000380460.3	Q9Y263
	PLAA	ENST00000970093.1		c.68dupG	p.Leu24ProfsTer55	frameshift	Exon 1 of 14	ENSP00000640152.1
	PLAA	ENST00000970089.1		c.68dupG	p.Leu24ProfsTer55	frameshift	Exon 1 of 14	ENSP00000640148.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1554662408; hg19: chr9-26946975;