rs147372600

chr5-13776568-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001369.3(DNAH5):c.9244C>A(p.Leu3082Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,613,940 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3082P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 8.03

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018675089).
• BP6: Variant 5-13776568-G-T is Benign according to our data. Variant chr5-13776568-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258067.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00173 (263/152294) while in subpopulation AFR AF= 0.00585 (243/41570). AF 95% confidence interval is 0.00524. There are 1 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.9244C>A	p.Leu3082Ile	missense_variant	55/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.9244C>A	p.Leu3082Ile	missense_variant	55/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.9199C>A	p.Leu3067Ile	missense_variant	55/79			A1

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 263 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000622 AC: 156 AN: 250970 Hom.: 0 AF XY: 0.000546 AC XY: 74 AN XY: 135608

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000244 AC: 357 AN: 1461646 Hom.: 0 Cov.: 33 AF XY: 0.000212 AC XY: 154 AN XY: 727136

Gnomad4 AFR exome AF: 0.00484

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00173 AC: 263 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74470

Gnomad4 AFR AF: 0.00585

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000530 Hom.: 0

Bravo AF: 0.00189

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 07, 2020	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 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

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	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.79
MPC		0.35
ClinPred		0.064	T
GERP RS		5.8
Varity_R		0.81
gMVP		0.65

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: rs147372600; hg19: chr5-13776677;