rs116401640

Positions:

• chr6-38886869-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001206927.2(DNAH8):​c.8338A>G​(p.Ile2780Val) variant causes a missense change. The variant allele was found at a frequency of 0.000687 in 1,614,066 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2780T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.31

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008222312).
• BP6: Variant 6-38886869-A-G is Benign according to our data. Variant chr6-38886869-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 414383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00391 (596/152306) while in subpopulation AFR AF= 0.014 (582/41564). AF 95% confidence interval is 0.0131. There are 5 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.8338A>G	p.Ile2780Val	missense_variant	57/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.8338A>G	p.Ile2780Val	missense_variant	57/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.7687A>G	p.Ile2563Val	missense_variant	55/91	2		A2
DNAH8	ENST00000449981.6	c.8338A>G	p.Ile2780Val	missense_variant	56/82	5

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152188 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000912 AC: 229 AN: 251152 Hom.: 3 AF XY: 0.000678 AC XY: 92 AN XY: 135724

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000351 AC: 513 AN: 1461760 Hom.: 3 Cov.: 31 AF XY: 0.000311 AC XY: 226 AN XY: 727188

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00391 AC: 596 AN: 152306 Hom.: 5 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74472

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000611 Hom.: 0

Bravo AF: 0.00404

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00114 AC: 139

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

DNAH8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0082	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Uncertain	0.51	T
REVEL	Benign	0.064
Polyphen		0.48	.;.;P
Vest4		0.42
MVP		0.40
MPC		0.11
ClinPred		0.033	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116401640; hg19: chr6-38854645;