rs1303708125

Variant names:

• chr5-13886135-C-A
• rs1303708125
• NM_001369.3:c.2578-6G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001369.3(DNAH5):​c.2578-6G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,217,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAH5 NM_001369.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001886
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.39
• Publications: 0 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

ENSG00000251423 (HGNC:40187):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-13886135-C-A is Benign according to our data. Variant chr5-13886135-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 454759.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.2578-6G>T		splice_region_variant, intron_variant	Intron 17 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.2578-6G>T		splice_region_variant, intron_variant	Intron 17 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.2533-6G>T		splice_region_variant, intron_variant	Intron 17 of 78			ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.254-10454C>A		intron_variant	Intron 1 of 2	4
ENSG00000251423	ENST00000637153.1	n.214-10454C>A		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 214 AN: 123602 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00139

Gnomad AMI AF: 0.00369

Gnomad AMR AF: 0.00175

Gnomad ASJ AF: 0.000999

Gnomad EAS AF: 0.00420

Gnomad SAS AF: 0.000775

Gnomad FIN AF: 0.00100

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00189

Gnomad OTH AF: 0.00302

GnomAD4 exome AF: 0.00123 AC: 1495 AN: 1217844 Hom.: 0 Cov.: 24 AF XY: 0.00134 AC XY: 807 AN XY: 602144

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000822 AC: 22 AN: 26770

American (AMR) AF: 0.00256 AC: 70 AN: 27396

Ashkenazi Jewish (ASJ) AF: 0.00235 AC: 49 AN: 20874

East Asian (EAS) AF: 0.00273 AC: 90 AN: 32968

South Asian (SAS) AF: 0.00325 AC: 213 AN: 65456

European-Finnish (FIN) AF: 0.00191 AC: 60 AN: 31342

Middle Eastern (MID) AF: 0.00169 AC: 6 AN: 3548

European-Non Finnish (NFE) AF: 0.000953 AC: 914 AN: 958612

Other (OTH) AF: 0.00140 AC: 71 AN: 50878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00174 AC: 215 AN: 123580 Hom.: 0 Cov.: 18 AF XY: 0.00162 AC XY: 95 AN XY: 58606

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00139 AC: 47 AN: 33742

American (AMR) AF: 0.00175 AC: 21 AN: 12028

Ashkenazi Jewish (ASJ) AF: 0.000999 AC: 3 AN: 3004

East Asian (EAS) AF: 0.00421 AC: 15 AN: 3560

South Asian (SAS) AF: 0.00104 AC: 4 AN: 3846

European-Finnish (FIN) AF: 0.00100 AC: 6 AN: 5980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00189 AC: 111 AN: 58712

Other (OTH) AF: 0.00301 AC: 5 AN: 1660

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00228 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.13
DANN	Benign	0.76
PhyloP100		-1.4
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0080
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

Other links and lift over

dbSNP: rs1303708125; hg19: chr5-13886244;