7-761769-G-A

Position:

• chr7-761769-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_017802.4(DNAAF5):​c.1487G>A​(p.Arg496His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000859 in 1,606,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.715

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017632425).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000894 (130/1454126) while in subpopulation MID AF= 0.00468 (26/5556). AF 95% confidence interval is 0.00328. There are 0 homozygotes in gnomad4_exome. There are 66 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF5	NM_017802.4	c.1487G>A	p.Arg496His	missense_variant	7/13	ENST00000297440.11	NP_060272.3
DNAAF5	XM_024446813.2	c.1487G>A	p.Arg496His	missense_variant	7/12		XP_024302581.1
DNAAF5	NR_075098.2	n.1447G>A		non_coding_transcript_exon_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1487G>A	p.Arg496His	missense_variant	7/13	1	NM_017802.4	ENSP00000297440.6
DNAAF5	ENST00000440747.5	c.890G>A	p.Arg297His	missense_variant	7/13	2		ENSP00000403165.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000195 AC: 46 AN: 236202 Hom.: 0 AF XY: 0.000164 AC XY: 21 AN XY: 127972

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000240

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.0000571

Gnomad SAS exome AF: 0.0000696

Gnomad FIN exome AF: 0.0000500

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.0000894 AC: 130 AN: 1454126 Hom.: 0 Cov.: 31 AF XY: 0.0000913 AC XY: 66 AN XY: 722672

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000205

Gnomad4 ASJ exome AF: 0.000654

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000591

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000433

Gnomad4 OTH exome AF: 0.000300

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74506

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 18 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 13, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Primary ciliary dyskinesia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 04, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 496 of the DNAAF5 protein (p.Arg496His). This variant is present in population databases (rs149610399, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with DNAAF5-related conditions. ClinVar contains an entry for this variant (Variation ID: 410306). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.0
DANN	Benign	0.97
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.014
Sift	Benign	0.25	T
Sift4G	Benign	0.31	T
Polyphen		0.0050	B
Vest4		0.068
MVP		0.030
MPC		0.20
ClinPred		0.032	T
GERP RS		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.014
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149610399; hg19: chr7-801406; COSMIC: COSV52421420; COSMIC: COSV52421420;