rs886038637

Variant names:

• chr7-727333-C-T
• rs886038637
• NM_017802.4:c.595+18C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_017802.4(DNAAF5):​c.595+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,235,398 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: DNAAF5 NM_017802.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.19
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 7-727333-C-T is Benign according to our data. Variant chr7-727333-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 260935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.595+18C>T		intron	N/A	NP_060272.3
	PRKAR1B	NM_001164758.2		c.-23+257G>A		intron	N/A	NP_001158230.1
	PRKAR1B	NM_001164759.1		c.-23+322G>A		intron	N/A	NP_001158231.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.595+18C>T		intron	N/A	ENSP00000297440.6
	PRKAR1B	ENST00000403562.5	TSL:1	c.-23+257G>A		intron	N/A	ENSP00000385349.1
	PRKAR1B	ENST00000417852.5	TSL:2	c.-146G>A		5_prime_UTR	Exon 1 of 5	ENSP00000406670.1

Frequencies

GnomAD3 genomes AF: 0.0000865 AC: 13 AN: 150224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000487

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: 0.000164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 80 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 166 AN: 1085064 Hom.: 1 Cov.: 21 AF XY: 0.000152 AC XY: 79 AN XY: 519846

African (AFR) AF: 0.00 AC: 0 AN: 21936

American (AMR) AF: 0.00 AC: 0 AN: 7826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14086

East Asian (EAS) AF: 0.00 AC: 0 AN: 25000

South Asian (SAS) AF: 0.00 AC: 0 AN: 33424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2904

European-Non Finnish (NFE) AF: 0.000169 AC: 154 AN: 912984

Other (OTH) AF: 0.000278 AC: 12 AN: 43168

GnomAD4 genome AF: 0.0000865 AC: 13 AN: 150334 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 8 AN XY: 73324

African (AFR) AF: 0.0000485 AC: 2 AN: 41212

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	5.0
DANN	Benign	0.82
PhyloP100		1.2
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2

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: rs886038637; hg19: chr7-766970;