6-38984227-C-T

Variant names:

• chr6-38984227-C-T
• rs201329381
• NM_001206927.2:c.12973C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001206927.2(DNAH8):​c.12973C>T​(p.Arg4325Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,596,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4325Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.12973C>T	p.Arg4325Trp	missense_variant	Exon 87 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.12973C>T	p.Arg4325Trp	missense_variant	Exon 87 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.12322C>T	p.Arg4108Trp	missense_variant	Exon 85 of 91	2		ENSP00000352312.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000838 AC: 21 AN: 250474 AF XY: 0.0000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000554

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000374 AC: 54 AN: 1444316 Hom.: 0 Cov.: 27 AF XY: 0.0000320 AC XY: 23 AN XY: 719550

Gnomad4 AFR exome AF: 0.0000604 AC: 2 AN: 33130

Gnomad4 AMR exome AF: 0.000359 AC: 16 AN: 44590

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26032

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39546

Gnomad4 SAS exome AF: 0.0000117 AC: 1 AN: 85726

Gnomad4 FIN exome AF: 0.0000374 AC: 2 AN: 53406

Gnomad4 NFE exome AF: 0.0000283 AC: 31 AN: 1096378

Gnomad4 Remaining exome AF: 0.0000335 AC: 2 AN: 59770

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000655 AC: 0.0000654965 AN: 0.0000654965

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.00019253 AN: 0.00019253

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000146985 AN: 0.0000146985

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4325 of the DNAH8 protein (p.Arg4325Trp). This variant is present in population databases (rs201329381, gnomAD 0.06%). 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: 525455). 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 C0"). 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	Pathogenic	0.74
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	4.2	.;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.1	.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0090	.;D
Polyphen		1.0	.;D
Vest4		0.73
MutPred		0.79		.;Loss of MoRF binding (P = 0.1859);
MVP		0.71
MPC		0.58
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.86
Mutation Taster		=68/32	polymorphism

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: rs201329381; hg19: chr6-38952003; COSMIC: COSV59442908;