rs78491700

chr7-785649-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_017802.4(DNAAF5):c.2564A>G(p.Gln855Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,612,814 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q855H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.31

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004091412).
• BP6: Variant 7-785649-A-G is Benign according to our data. Variant chr7-785649-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 241203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00241 (367/152346) while in subpopulation AFR AF= 0.00851 (354/41598). AF 95% confidence interval is 0.00778. There are 2 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.2564A>G	p.Gln855Arg	missense_variant	13/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.2372A>G	p.Gln791Arg	missense_variant	12/12
DNAAF5	NR_075098.2	n.2524A>G		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.2564A>G	p.Gln855Arg	missense_variant	13/13	1	NM_017802.4	P1
DNAAF5	ENST00000403952.3	c.839A>G	p.Gln280Arg	missense_variant	6/6	1
DNAAF5	ENST00000440747.5	c.1970A>G	p.Gln657Arg	missense_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00849

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000643 AC: 161 AN: 250230 Hom.: 1 AF XY: 0.000465 AC XY: 63 AN XY: 135456

Gnomad AFR exome AF: 0.00923

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000216 AC: 316 AN: 1460468 Hom.: 0 Cov.: 33 AF XY: 0.000179 AC XY: 130 AN XY: 726498

Gnomad4 AFR exome AF: 0.00798

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00241 AC: 367 AN: 152346 Hom.: 2 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74498

Gnomad4 AFR AF: 0.00851

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000597 Hom.: 0

Bravo AF: 0.00287

ESP6500AA AF: 0.00886 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely 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	Invitae	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 24, 2018	This alteration is classified as likely 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.15
Dann	Benign	0.29
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.039
Sift	Benign	0.23	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0010	B;B
Vest4		0.083
MVP		0.030
MPC		0.18
ClinPred		0.0028	T
GERP RS		-6.1
Varity_R		0.021
gMVP		0.24

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: rs78491700; hg19: chr7-825286;