5-13717362-T-C

Variant names:

• chr5-13717362-T-C
• rs2277046
• NM_001369.3:c.12658A>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.12658A>G​(p.Thr4220Ala) variant causes a missense change. The variant allele was found at a frequency of 0.107 in 1,613,678 control chromosomes in the GnomAD database, including 14,021 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T4220T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.098 (1256 hom., cov: 32)
  • Exomes 𝑓: 0.11 (12765 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.14
• Publications: 35 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=0.0024172068).
• BP6: Variant 5-13717362-T-C is Benign according to our data. Variant chr5-13717362-T-C is described in ClinVar as Benign. ClinVar VariationId is 178741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.354 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.12658A>G	p.Thr4220Ala	missense	Exon 73 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.12658A>G	p.Thr4220Ala	missense	Exon 73 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.12613A>G	p.Thr4205Ala	missense	Exon 73 of 79	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes AF: 0.0984 AC: 14957 AN: 152060 Hom.: 1254 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.0692

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0869

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.149 AC: 37351 AN: 250530 AF XY: 0.144

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.0692

Gnomad EAS exome AF: 0.387

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.0834

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.108 AC: 158236 AN: 1461500 Hom.: 12765 Cov.: 33 AF XY: 0.109 AC XY: 79560 AN XY: 727028

African (AFR) AF: 0.0186 AC: 622 AN: 33478

American (AMR) AF: 0.300 AC: 13372 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0690 AC: 1804 AN: 26136

East Asian (EAS) AF: 0.427 AC: 16911 AN: 39632

South Asian (SAS) AF: 0.178 AC: 15382 AN: 86220

European-Finnish (FIN) AF: 0.140 AC: 7477 AN: 53390

Middle Eastern (MID) AF: 0.0330 AC: 190 AN: 5754

European-Non Finnish (NFE) AF: 0.0863 AC: 96009 AN: 1111868

Other (OTH) AF: 0.107 AC: 6469 AN: 60380

GnomAD4 genome AF: 0.0984 AC: 14970 AN: 152178 Hom.: 1256 Cov.: 32 AF XY: 0.105 AC XY: 7806 AN XY: 74402

African (AFR) AF: 0.0252 AC: 1048 AN: 41540

American (AMR) AF: 0.209 AC: 3197 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0692 AC: 240 AN: 3470

East Asian (EAS) AF: 0.368 AC: 1887 AN: 5132

South Asian (SAS) AF: 0.200 AC: 967 AN: 4824

European-Finnish (FIN) AF: 0.136 AC: 1443 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0869 AC: 5911 AN: 68012

Other (OTH) AF: 0.104 AC: 219 AN: 2112

Alfa AF: 0.0937 Hom.: 2583

Bravo AF: 0.103

TwinsUK AF: 0.0925 AC: 343

ALSPAC AF: 0.0921 AC: 355

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.0779 AC: 670

ExAC AF: 0.141 AC: 17075

Asia WGS AF: 0.260 AC: 901 AN: 3478

EpiCase AF: 0.0731

EpiControl AF: 0.0747

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.10	N
PhyloP100		5.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.060
Sift	Benign	0.046	D
Polyphen		0.0080	B
Vest4		0.25
MPC		0.26
ClinPred		0.029	T
GERP RS		4.3
Varity_R		0.41
gMVP		0.79
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2277046; hg19: chr5-13717471; COSMIC: COSV54217551;