rs114717951

Variant names:

• chr5-13900435-T-G
• rs114717951
• NM_001369.3:c.2053-23A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001369.3(DNAH5):​c.2053-23A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 1,592,814 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (117 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00300
• 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

ENSG00000251423 (HGNC:40187):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-13900435-T-G is Benign according to our data. Variant chr5-13900435-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00509 (775/152320) while in subpopulation SAS AF = 0.03 (145/4828). AF 95% confidence interval is 0.0261. There are 2 homozygotes in GnomAd4. There are 418 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.2053-23A>C		intron	N/A	NP_001360.1
	DNAH5-AS1	NR_199035.1		n.3175T>G		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.2053-23A>C		intron	N/A	ENSP00000265104.4
	ENSG00000251423	ENST00000503244.2	TSL:4	n.3311T>G		non_coding_transcript_exon	Exon 3 of 3
	ENSG00000251423	ENST00000637153.1	TSL:5	n.3271T>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 780 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0306

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00958 AC: 2382 AN: 248738 AF XY: 0.0111

Gnomad AFR exome AF: 0.000567

Gnomad AMR exome AF: 0.00528

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.00220

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.00727 AC: 10478 AN: 1440494 Hom.: 117 Cov.: 25 AF XY: 0.00843 AC XY: 6051 AN XY: 718114

African (AFR) AF: 0.00212 AC: 70 AN: 33048

American (AMR) AF: 0.00546 AC: 244 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 361 AN: 25978

East Asian (EAS) AF: 0.00116 AC: 46 AN: 39514

South Asian (SAS) AF: 0.0375 AC: 3214 AN: 85774

European-Finnish (FIN) AF: 0.00300 AC: 160 AN: 53322

Middle Eastern (MID) AF: 0.0410 AC: 232 AN: 5656

European-Non Finnish (NFE) AF: 0.00512 AC: 5597 AN: 1092858

Other (OTH) AF: 0.00929 AC: 554 AN: 59650

GnomAD4 genome AF: 0.00509 AC: 775 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.00561 AC XY: 418 AN XY: 74492

African (AFR) AF: 0.000938 AC: 39 AN: 41566

American (AMR) AF: 0.00758 AC: 116 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5186

South Asian (SAS) AF: 0.0300 AC: 145 AN: 4828

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00560 AC: 381 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00767 Hom.: 1

Bravo AF: 0.00465

Asia WGS AF: 0.0170 AC: 58 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.64
DANN	Benign	0.46
PhyloP100		-0.0030
La Branchor		0.54
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs114717951; hg19: chr5-13900544;