7-741343-T-G

Variant names:

• chr7-741343-T-G
• rs6943337
• NM_017802.4:c.906-4T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017802.4(DNAAF5):​c.906-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,585,028 control chromosomes in the GnomAD database, including 525,722 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46900 hom., cov: 35)
  • Exomes 𝑓: 0.82 (478822 hom.)
• Consequence: DNAAF5 NM_017802.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002695
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.09
• Publications: 11 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]

DNAAF5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 18

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 7-741343-T-G is Benign according to our data. Variant chr7-741343-T-G is described in ClinVar as Benign. ClinVar VariationId is 260939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF5	NM_017802.4	c.906-4T>G		splice_region_variant, intron_variant	Intron 3 of 12	ENST00000297440.11	NP_060272.3
DNAAF5	NR_075098.2	n.866-4T>G		splice_region_variant, intron_variant	Intron 3 of 12
DNAAF5	XM_024446813.2	c.906-4T>G		splice_region_variant, intron_variant	Intron 3 of 11		XP_024302581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11	c.906-4T>G		splice_region_variant, intron_variant	Intron 3 of 12	1	NM_017802.4	ENSP00000297440.6
DNAAF5	ENST00000440747.5	c.309-4T>G		splice_region_variant, intron_variant	Intron 3 of 12	2		ENSP00000403165.1
DNAAF5	ENST00000437419.5	c.222-4T>G		splice_region_variant, intron_variant	Intron 2 of 4	5		ENSP00000410788.1
DNAAF5	ENST00000438961.1	n.375-4T>G		splice_region_variant, intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118999 AN: 152116 Hom.: 46863 Cov.: 35

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.819

GnomAD2 exomes AF: 0.802 AC: 168499 AN: 210076 AF XY: 0.811

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.737

Gnomad ASJ exome AF: 0.860

Gnomad EAS exome AF: 0.654

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.837

Gnomad OTH exome AF: 0.832

GnomAD4 exome AF: 0.816 AC: 1169273 AN: 1432796 Hom.: 478822 Cov.: 32 AF XY: 0.818 AC XY: 580841 AN XY: 710182

African (AFR) AF: 0.715 AC: 23680 AN: 33110

American (AMR) AF: 0.745 AC: 29853 AN: 40090

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 21930 AN: 25540

East Asian (EAS) AF: 0.607 AC: 23526 AN: 38732

South Asian (SAS) AF: 0.865 AC: 70979 AN: 82012

European-Finnish (FIN) AF: 0.773 AC: 39814 AN: 51476

Middle Eastern (MID) AF: 0.853 AC: 3680 AN: 4314

European-Non Finnish (NFE) AF: 0.827 AC: 907827 AN: 1098312

Other (OTH) AF: 0.810 AC: 47984 AN: 59210

GnomAD4 genome AF: 0.782 AC: 119092 AN: 152232 Hom.: 46900 Cov.: 35 AF XY: 0.780 AC XY: 58057 AN XY: 74430

African (AFR) AF: 0.710 AC: 29494 AN: 41516

American (AMR) AF: 0.813 AC: 12451 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2968 AN: 3472

East Asian (EAS) AF: 0.629 AC: 3249 AN: 5164

South Asian (SAS) AF: 0.872 AC: 4211 AN: 4830

European-Finnish (FIN) AF: 0.767 AC: 8141 AN: 10612

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.821 AC: 55817 AN: 68010

Other (OTH) AF: 0.822 AC: 1736 AN: 2112

Alfa AF: 0.802 Hom.: 17624

Bravo AF: 0.781

Asia WGS AF: 0.778 AC: 2707 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Primary ciliary dyskinesia 18 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.14
DANN	Benign	0.30
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0020
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: rs6943337; hg19: chr7-780980; COSMIC: COSV52417763;