5-13824227-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001369.3(DNAH5):c.6551T>A(p.Val2184Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2184A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.6551T>A	p.Val2184Glu	missense_variant	39/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.6551T>A	p.Val2184Glu	missense_variant	39/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.6506T>A	p.Val2169Glu	missense_variant	39/79			A1
DNAH5	ENST00000683090.1	n.1482T>A		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251354 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.014	D
Polyphen		0.98	D
Vest4		0.93
MutPred		0.74		Gain of disorder (P = 0.019);
MVP		0.66
MPC		0.31
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.76
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs200805455; hg19: chr5-13824336; COSMIC: COSV54202341;