chr7-727176-C-A

Variant names:

• chr7-727176-C-A
• rs769656987
• NM_017802.4:c.456C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_017802.4(DNAAF5):​c.456C>A​(p.Ala152Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 1,334,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A152A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	NM_017802.4	MANE Select	c.456C>A	p.Ala152Ala	synonymous	Exon 1 of 13	NP_060272.3
	PRKAR1B	NM_001164760.2	MANE Select	c.-23+34G>T		intron	N/A	NP_001158232.1
	DNAAF5	NR_075098.2		n.478C>A		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.456C>A	p.Ala152Ala	synonymous	Exon 1 of 13	ENSP00000297440.6
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+34G>T		intron	N/A	ENSP00000440449.1
	PRKAR1B	ENST00000403562.5	TSL:1	c.-23+414G>T		intron	N/A	ENSP00000385349.1

Frequencies

GnomAD3 genomes AF: 0.00000669 AC: 1 AN: 149554 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000253 AC: 3 AN: 1185320 Hom.: 0 Cov.: 31 AF XY: 0.00000344 AC XY: 2 AN XY: 581490

African (AFR) AF: 0.00 AC: 0 AN: 23614

American (AMR) AF: 0.00 AC: 0 AN: 17462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18232

East Asian (EAS) AF: 0.00 AC: 0 AN: 23752

South Asian (SAS) AF: 0.00 AC: 0 AN: 54346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3226

European-Non Finnish (NFE) AF: 0.00000309 AC: 3 AN: 971352

Other (OTH) AF: 0.00 AC: 0 AN: 46490

GnomAD4 genome AF: 0.00000669 AC: 1 AN: 149554 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72908

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

African (AFR) AF: 0.0000243 AC: 1 AN: 41122

American (AMR) AF: 0.00 AC: 0 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66886

Other (OTH) AF: 0.00 AC: 0 AN: 2050

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.4
DANN	Benign	0.68
PhyloP100		-1.6
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9

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: rs769656987; hg19: chr7-766813;