rs148767488

chr6-38848787-A-Cchr6-38848787-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001206927.2(DNAH8):c.5185A>C(p.Lys1729Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.11

Genes affected

DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35040247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.5185A>C	p.Lys1729Gln	missense_variant	37/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.5185A>C	p.Lys1729Gln	missense_variant	37/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.4534A>C	p.Lys1512Gln	missense_variant	35/91	2		A2
DNAH8	ENST00000449981.6	c.5185A>C	p.Lys1729Gln	missense_variant	36/82	5

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 250944 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135626

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000296 AC: 433 AN: 1461142 Hom.: 0 Cov.: 30 AF XY: 0.000277 AC XY: 201 AN XY: 726880

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000361

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74454

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000288 Hom.: 1

Bravo AF: 0.000291

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Oct 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 05, 2022	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1729 of the DNAH8 protein (p.Lys1729Gln). This variant is present in population databases (rs148767488, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 407298). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C45"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.5185A>C (p.K1729Q) alteration is located in exon 37 (coding exon 36) of the DNAH8 gene. This alteration results from a A to C substitution at nucleotide position 5185, causing the lysine (K) at amino acid position 1729 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.095	T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
REVEL	Uncertain	0.49
Polyphen		1.0	.;.;D
Vest4		0.59
MVP		0.78
MPC		0.59
ClinPred		0.35	T
GERP RS		5.8
Varity_R		0.76
gMVP		0.33

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: rs148767488; hg19: chr6-38816563;