rs77384933

Positions:

• chr7-754620-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000297440.11(DNAAF5):​c.1056C>T​(p.Leu352=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,096 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (30 hom.)
• Consequence: DNAAF5 ENST00000297440.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.826

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 7-754620-C-T is Benign according to our data. Variant chr7-754620-C-T is described in ClinVar as [Benign]. Clinvar id is 260921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.826 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00933 (1421/152282) while in subpopulation AFR AF= 0.0212 (880/41556). AF 95% confidence interval is 0.02. There are 16 homozygotes in gnomad4. There are 634 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF5	NM_017802.4	c.1056C>T	p.Leu352=	synonymous_variant	5/13	ENST00000297440.11	NP_060272.3
DNAAF5	XM_024446813.2	c.1056C>T	p.Leu352=	synonymous_variant	5/12		XP_024302581.1
DNAAF5	NR_075098.2	n.1016C>T		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1056C>T	p.Leu352=	synonymous_variant	5/13	1	NM_017802.4	ENSP00000297440	P1
DNAAF5	ENST00000440747.5	c.462C>T	p.Leu154=	synonymous_variant	5/13	2		ENSP00000403165
DNAAF5	ENST00000437419.5	c.375C>T	p.Leu125=	synonymous_variant	4/5	5		ENSP00000410788

Frequencies

GnomAD3 genomes AF: 0.00934 AC: 1421 AN: 152164 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00476 AC: 1195 AN: 251074 Hom.: 9 AF XY: 0.00422 AC XY: 572 AN XY: 135690

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00709

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00767

GnomAD4 exome AF: 0.00304 AC: 4446 AN: 1461814 Hom.: 30 Cov.: 32 AF XY: 0.00295 AC XY: 2145 AN XY: 727196

Gnomad4 AFR exome AF: 0.0208

Gnomad4 AMR exome AF: 0.00702

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00616

GnomAD4 genome AF: 0.00933 AC: 1421 AN: 152282 Hom.: 16 Cov.: 32 AF XY: 0.00852 AC XY: 634 AN XY: 74452

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00646 Hom.: 4

Bravo AF: 0.0106

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 19, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.67
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs77384933; hg19: chr7-794257; COSMIC: COSV104619087; COSMIC: COSV104619087;