rs1217845018

Variant names:

• chr7-726770-AG-A
• rs1217845018
• NM_017802.4:c.55delG

Your query was ambiguous. Multiple possible variants found:

• chr7-726770-AG-A
• chr7-726770-AG-AGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_017802.4(DNAAF5):​c.55delG​(p.Ala19ProfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000901 in 1,109,776 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.121
• Publications: 0 publications found

Genes affected

DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

PRKAR1B (HGNC:9390): (protein kinase cAMP-dependent type I regulatory subunit beta) The protein encoded by this gene is a regulatory subunit of cyclic AMP-dependent protein kinase A (PKA), which is involved in the signaling pathway of the second messenger cAMP. Two regulatory and two catalytic subunits form the PKA holoenzyme, disbands after cAMP binding. The holoenzyme is involved in many cellular events, including ion transport, metabolism, and transcription. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2015]

PRKAR1B Gene-Disease associations (from GenCC):

• Marbach-Schaaf neurodevelopmental syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• PRKAR1B-related neurodegenerative dementia with intermediate filaments

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 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 39 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017802.4. 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
	DNAAF5	NM_017802.4	MANE Select	c.55delG	p.Ala19ProfsTer9	frameshift	Exon 1 of 13	NP_060272.3
	PRKAR1B	NM_001164760.2	MANE Select	c.-23+439delC		intron	N/A	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.-23+819delC		intron	N/A	NP_001158230.1	P31321

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.55delG	p.Ala19ProfsTer9	frameshift	Exon 1 of 13	ENSP00000297440.6	Q86Y56-1
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+439delC		intron	N/A	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.-23+819delC		intron	N/A	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.01e-7 AC: 1 AN: 1109776 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 528734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23042

American (AMR) AF: 0.00 AC: 0 AN: 8520

Ashkenazi Jewish (ASJ) AF: 0.0000677 AC: 1 AN: 14766

East Asian (EAS) AF: 0.00 AC: 0 AN: 26684

South Asian (SAS) AF: 0.00 AC: 0 AN: 28384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3038

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 937540

Other (OTH) AF: 0.00 AC: 0 AN: 44800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12

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: rs1217845018; hg19: chr7-766407;