chr5-13780918-C-A

Variant names:

• chr5-13780918-C-A
• rs145381989
• NM_001369.3:c.8862G>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001369.3(DNAH5):​c.8862G>T​(p.Leu2954Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,613,764 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.13

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 5-13780918-C-A is Benign according to our data. Variant chr5-13780918-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 414346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0011 (167/152312) while in subpopulation AFR AF= 0.00361 (150/41564). AF 95% confidence interval is 0.00314. There are 2 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.8862G>T	p.Leu2954Leu	synonymous_variant	Exon 53 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.8862G>T	p.Leu2954Leu	synonymous_variant	Exon 53 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.8817G>T	p.Leu2939Leu	synonymous_variant	Exon 53 of 79			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 250942 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135608

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000116 AC: 170 AN: 1461452 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 727042

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74478

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000444 Hom.: 0

Bravo AF: 0.00123

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Aug 07, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DNAH5-related disorder Benign:1

Nov 13, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.44
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145381989; hg19: chr5-13781027; COSMIC: COSV54215619;