rs377367981

Variant names:

• chr5-13807734-G-C
• rs377367981
• NM_001369.3:c.7753-9C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001369.3(DNAH5):​c.7753-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,597,504 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).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Scores: Splicing: ADA: 0.001087
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0530
• 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-13807734-G-C is Benign according to our data. Variant chr5-13807734-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258060.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0011 (167/152142) while in subpopulation AFR AF = 0.00393 (163/41512). AF 95% confidence interval is 0.00343. There are 1 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.7753-9C>G		intron	N/A	NP_001360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.7753-9C>G		intron	N/A	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.7708-9C>G		intron	N/A	ENSP00000505288.1
	DNAH5	ENST00000512443.1	TSL:3	n.609-9C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152024 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000207 AC: 47 AN: 226748 AF XY: 0.000156

Gnomad AFR exome AF: 0.00311

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 191 AN: 1445362 Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 92 AN XY: 717770

African (AFR) AF: 0.00512 AC: 170 AN: 33186

American (AMR) AF: 0.0000464 AC: 2 AN: 43114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 84152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101620

Other (OTH) AF: 0.000285 AC: 17 AN: 59732

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152142 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74376

African (AFR) AF: 0.00393 AC: 163 AN: 41512

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.00124

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (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	0.0060
DANN	Benign	0.37
PhyloP100		-0.053

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.044
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

Other links and lift over

dbSNP: rs377367981; hg19: chr5-13807843;