rs139564138

Variant names:

• chr6-38899879-A-G
• rs139564138
• NM_001206927.2:c.9167A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001206927.2(DNAH8):​c.9167A>G​(p.Tyr3056Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,605,754 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.9167A>G	p.Tyr3056Cys	missense_variant	Exon 62 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.9167A>G	p.Tyr3056Cys	missense_variant	Exon 62 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.8516A>G	p.Tyr2839Cys	missense_variant	Exon 60 of 91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.9167A>G	p.Tyr3056Cys	missense_variant	Exon 61 of 82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000235

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000149 AC: 36 AN: 241614 Hom.: 1 AF XY: 0.000168 AC XY: 22 AN XY: 130590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000310

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: 0.000208

Gnomad OTH exome AF: 0.000510

GnomAD4 exome AF: 0.000193 AC: 280 AN: 1453518 Hom.: 1 Cov.: 30 AF XY: 0.000183 AC XY: 132 AN XY: 722730

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.000397

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: 0.000224

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74374

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Oct 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3056 of the DNAH8 protein (p.Tyr3056Cys). This variant is present in population databases (rs139564138, 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: 525448). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAH8 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.6	.;.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.7	.;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	.;D;D
Polyphen		1.0	.;.;D
Vest4		0.88
MVP		0.93
MPC		0.64
ClinPred		0.49	T
GERP RS		6.2
Varity_R		0.75
gMVP		0.78

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: rs139564138; hg19: chr6-38867655;