rs146922072

chr7-754809-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 NM_017802.4(DNAAF5):c.1245C>T(p.Ala415=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,604,072 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: DNAAF5 NM_017802.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.14

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=-0.62).
• BP6: Variant 7-754809-C-T is Benign according to our data. Variant chr7-754809-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00174 (265/152314) while in subpopulation AMR AF= 0.00137 (21/15298). AF 95% confidence interval is 0.000919. There are 2 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.1245C>T	p.Ala415=	synonymous_variant	5/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.1245C>T	p.Ala415=	synonymous_variant	5/12
DNAAF5	NR_075098.2	n.1205C>T		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1245C>T	p.Ala415=	synonymous_variant	5/13	1	NM_017802.4	P1
DNAAF5	ENST00000440747.5	c.651C>T	p.Ala217=	synonymous_variant	5/13	2
DNAAF5	ENST00000437419.5	c.564C>T	p.Ala188=	synonymous_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152196 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00276 AC: 666 AN: 241656 Hom.: 10 AF XY: 0.00268 AC XY: 352 AN XY: 131580

Gnomad AFR exome AF: 0.000836

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.0483

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000802

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00145 AC: 2099 AN: 1451758 Hom.: 35 Cov.: 32 AF XY: 0.00148 AC XY: 1068 AN XY: 720520

Gnomad4 AFR exome AF: 0.000931

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.0499

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000382

Gnomad4 OTH exome AF: 0.00410

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152314 Hom.: 2 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74474

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.0533

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00475 Hom.: 3

Bravo AF: 0.00201

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2017	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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

DNAAF5: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.94
Dann	Benign	0.69

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: rs146922072; hg19: chr7-794446; COSMIC: COSV52418540; COSMIC: COSV52418540;