5-13701427-T-C

Variant names:

• chr5-13701427-T-C
• rs3734110
• NM_001369.3:c.13348A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.13348A>G​(p.Ile4450Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,602,296 control chromosomes in the GnomAD database, including 233,685 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4450F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.53 (21311 hom., cov: 30)
  • Exomes 𝑓: 0.54 (212374 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.805
• Publications: 32 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.3269225E-5).
• BP6: Variant 5-13701427-T-C is Benign according to our data. Variant chr5-13701427-T-C is described in ClinVar as Benign. ClinVar VariationId is 163132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

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.13348A>G	p.Ile4450Val	missense	Exon 77 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.13348A>G	p.Ile4450Val	missense	Exon 77 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.13303A>G	p.Ile4435Val	missense	Exon 77 of 79	ENSP00000505288.1	A0A7P0Z455
	DNAH5	ENST00000683611.1		n.681A>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80024 AN: 151236 Hom.: 21282 Cov.: 30

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.518 AC: 130100 AN: 250968 AF XY: 0.516

Gnomad AFR exome AF: 0.518

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.541

Gnomad EAS exome AF: 0.422

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.538 AC: 780975 AN: 1450940 Hom.: 212374 Cov.: 41 AF XY: 0.535 AC XY: 386771 AN XY: 722426

African (AFR) AF: 0.506 AC: 16865 AN: 33304

American (AMR) AF: 0.508 AC: 22690 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 14039 AN: 26082

East Asian (EAS) AF: 0.406 AC: 16077 AN: 39630

South Asian (SAS) AF: 0.455 AC: 39134 AN: 86030

European-Finnish (FIN) AF: 0.529 AC: 28229 AN: 53410

Middle Eastern (MID) AF: 0.543 AC: 3125 AN: 5756

European-Non Finnish (NFE) AF: 0.553 AC: 609023 AN: 1101986

Other (OTH) AF: 0.530 AC: 31793 AN: 60036

GnomAD4 genome AF: 0.529 AC: 80104 AN: 151356 Hom.: 21311 Cov.: 30 AF XY: 0.526 AC XY: 38835 AN XY: 73884

African (AFR) AF: 0.517 AC: 21323 AN: 41216

American (AMR) AF: 0.522 AC: 7946 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1911 AN: 3468

East Asian (EAS) AF: 0.442 AC: 2273 AN: 5142

South Asian (SAS) AF: 0.455 AC: 2184 AN: 4804

European-Finnish (FIN) AF: 0.532 AC: 5532 AN: 10394

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.547 AC: 37109 AN: 67822

Other (OTH) AF: 0.538 AC: 1128 AN: 2098

Alfa AF: 0.541 Hom.: 73904

Bravo AF: 0.530

TwinsUK AF: 0.549 AC: 2034

ALSPAC AF: 0.552 AC: 2127

ESP6500AA AF: 0.505 AC: 2223

ESP6500EA AF: 0.550 AC: 4726

ExAC AF: 0.518 AC: 62936

Asia WGS AF: 0.473 AC: 1648 AN: 3478

EpiCase AF: 0.544

EpiControl AF: 0.556

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Primary ciliary dyskinesia (3)
-	-	3	Primary ciliary dyskinesia 3 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.5
DANN	Benign	0.95
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.000053	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.17	N
PhyloP100		0.81
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.062
Sift	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.078
ClinPred		0.0030	T
GERP RS		4.9
Varity_R		0.060
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs3734110; hg19: chr5-13701536; COSMIC: COSV54212359;