chr9-26946978-C-A

Variant names:

• chr9-26946978-C-A
• rs747956857
• NM_001031689.3:c.68G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001031689.3(PLAA):​c.68G>T​(p.Gly23Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLAA NM_001031689.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.63
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847
• PP5: Variant 9-26946978-C-A is Pathogenic according to our data. Variant chr9-26946978-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 427941.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.68G>T	p.Gly23Val	missense	Exon 1 of 14	NP_001026859.1	Q9Y263
	PLAA	NM_001321546.2		c.68G>T	p.Gly23Val	missense	Exon 1 of 13	NP_001308475.1
	IFT74	NM_001099223.3		c.-188C>A		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.68G>T	p.Gly23Val	missense	Exon 1 of 14	ENSP00000380460.3	Q9Y263
	PLAA	ENST00000970093.1		c.68G>T	p.Gly23Val	missense	Exon 1 of 14	ENSP00000640152.1
	PLAA	ENST00000970089.1		c.68G>T	p.Gly23Val	missense	Exon 1 of 14	ENSP00000640148.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440344 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714618

African (AFR) AF: 0.00 AC: 0 AN: 33024

American (AMR) AF: 0.00 AC: 0 AN: 42084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 38452

South Asian (SAS) AF: 0.00 AC: 0 AN: 82824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102192

Other (OTH) AF: 0.00 AC: 0 AN: 59482

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000829 AC: 1

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
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.92
MutPred		0.47		Loss of disorder (P = 0.2009)
MVP		0.84
MPC		2.6
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.28	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.70
gMVP		0.76
Mutation Taster		=15/85	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs747956857; hg19: chr9-26946976;