rs1060501454

Variant names:

• chr5-13780960-C-A
• rs1060501454
• NM_001369.3:c.8821-1G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-13780960-C-A
• chr5-13780960-C-G
• chr5-13780960-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_001369.3(DNAH5):​c.8821-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000411 in 1,461,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DNAH5 NM_001369.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.05
• Publications: 2 publications found

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]

DNAH5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 3

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009441442 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.6, offset of 27, new splice context is: gtgtcattcgtactcctcAGgga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 5-13780960-C-A is Pathogenic according to our data. Variant chr5-13780960-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1076155.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.8821-1G>T		splice_acceptor_variant, intron_variant	Intron 52 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.8821-1G>T		splice_acceptor_variant, intron_variant	Intron 52 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.8776-1G>T		splice_acceptor_variant, intron_variant	Intron 52 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250830 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461252 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726948

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111626

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 52 of the DNAH5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). ClinVar contains an entry for this variant (Variation ID: 1076155). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.0
GERP RS		5.6
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.50		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060501454; hg19: chr5-13781069;