chr5-13841895-G-C

Variant names:

• chr5-13841895-G-C
• rs148891849
• NM_001369.3:c.5281C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS1

The NM_001369.3(DNAH5):​c.5281C>G​(p.Arg1761Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000657 in 1,093,802 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1761Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 25)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.99
• Publications: 5 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 6 uncertain in NM_001369.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.015398979).
• BP6: Variant 5-13841895-G-C is Benign according to our data. Variant chr5-13841895-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00345 (376/108914) while in subpopulation AFR AF = 0.0129 (361/28086). AF 95% confidence interval is 0.0118. There are 1 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 25. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.5281C>G	p.Arg1761Gly	missense	Exon 33 of 79	NP_001360.1	Q8TE73

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.5281C>G	p.Arg1761Gly	missense	Exon 33 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.5236C>G	p.Arg1746Gly	missense	Exon 33 of 79	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 373 AN: 108868 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

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: 0.0000343

Gnomad OTH AF: 0.000711

GnomAD2 exomes AF: 0.000804 AC: 186 AN: 231214 AF XY: 0.000629

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000950

Gnomad OTH exome AF: 0.000736

GnomAD4 exome AF: 0.000348 AC: 343 AN: 984888 Hom.: 1 Cov.: 26 AF XY: 0.000300 AC XY: 151 AN XY: 502836

African (AFR) AF: 0.0129 AC: 303 AN: 23544

American (AMR) AF: 0.000350 AC: 14 AN: 40024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19594

East Asian (EAS) AF: 0.00 AC: 0 AN: 28278

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44288

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4064

European-Non Finnish (NFE) AF: 0.00000423 AC: 3 AN: 709508

Other (OTH) AF: 0.000512 AC: 21 AN: 41016

GnomAD4 genome AF: 0.00345 AC: 376 AN: 108914 Hom.: 1 Cov.: 25 AF XY: 0.00329 AC XY: 162 AN XY: 49222

African (AFR) AF: 0.0129 AC: 361 AN: 28086

American (AMR) AF: 0.00159 AC: 12 AN: 7558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3172

East Asian (EAS) AF: 0.00 AC: 0 AN: 3592

South Asian (SAS) AF: 0.00 AC: 0 AN: 3068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 98

European-Non Finnish (NFE) AF: 0.0000343 AC: 2 AN: 58328

Other (OTH) AF: 0.000708 AC: 1 AN: 1412

Alfa AF: 0.000150 Hom.: 1

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000947 AC: 115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.0
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.15
Sift	Uncertain	0.011	D
Polyphen		0.78	P
Vest4		0.88
MVP		0.57
MPC		0.33
ClinPred		0.12	T
GERP RS		5.1
Varity_R		0.64
gMVP		0.69
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148891849; hg19: chr5-13842004;