rs4720951

chr7-770582-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017802.4(DNAAF5):c.1895T>C(p.Val632Ala) variant causes a missense change. The variant allele was found at a frequency of 0.454 in 1,613,284 control chromosomes in the GnomAD database, including 168,411 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14620 hom., cov: 34)
  • Exomes 𝑓: 0.46 (153791 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.94

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004177332).
• BP6: Variant 7-770582-T-C is Benign according to our data. Variant chr7-770582-T-C is described in ClinVar as [Benign]. Clinvar id is 260930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.1895T>C	p.Val632Ala	missense_variant	9/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.1895T>C	p.Val632Ala	missense_variant	9/12
DNAAF5	NR_075098.2	n.1855T>C		non_coding_transcript_exon_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1895T>C	p.Val632Ala	missense_variant	9/13	1	NM_017802.4	P1
DNAAF5	ENST00000403952.3	c.170T>C	p.Val57Ala	missense_variant	2/6	1
DNAAF5	ENST00000440747.5	c.1301T>C	p.Val434Ala	missense_variant	9/13	2
DNAAF5	ENST00000491496.1	n.180T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65803 AN: 152002 Hom.: 14599 Cov.: 34

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.457

GnomAD3 exomes AF: 0.434 AC: 108814 AN: 250670 Hom.: 24037 AF XY: 0.434 AC XY: 58900 AN XY: 135630

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.338

Gnomad SAS exome AF: 0.366

Gnomad FIN exome AF: 0.514

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.457 AC: 667023 AN: 1461164 Hom.: 153791 Cov.: 49 AF XY: 0.455 AC XY: 330459 AN XY: 726926

Gnomad4 AFR exome AF: 0.355

Gnomad4 AMR exome AF: 0.408

Gnomad4 ASJ exome AF: 0.463

Gnomad4 EAS exome AF: 0.320

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.513

Gnomad4 NFE exome AF: 0.471

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.433 AC: 65858 AN: 152120 Hom.: 14620 Cov.: 34 AF XY: 0.432 AC XY: 32165 AN XY: 74390

Gnomad4 AFR AF: 0.358

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.459

Alfa AF: 0.460 Hom.: 24627

Bravo AF: 0.427

TwinsUK AF: 0.454 AC: 1685

ALSPAC AF: 0.482 AC: 1859

ESP6500AA AF: 0.356 AC: 1569

ESP6500EA AF: 0.471 AC: 4049

ExAC AF: 0.429 AC: 52105

Asia WGS AF: 0.414 AC: 1440 AN: 3478

EpiCase AF: 0.482

EpiControl AF: 0.484

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Primary ciliary dyskinesia 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	18
Dann	Benign	0.82
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.97	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.18
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.013	D;D
Polyphen		0.014	B;B
Vest4		0.12
MPC		0.20
ClinPred		0.016	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.28

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: rs4720951; hg19: chr7-810219; COSMIC: COSV52413848;