rs61758415

chr6-38852754-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001206927.2(DNAH8):c.5527G>C(p.Asp1843His) variant causes a missense change. The variant allele was found at a frequency of 0.000326 in 1,613,796 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1843G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.45

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013608336).
• BP6: Variant 6-38852754-G-C is Benign according to our data. Variant chr6-38852754-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 454581.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 = 0.00187 (285/152278) while in subpopulation AFR AF= 0.00645 (268/41538). AF 95% confidence interval is 0.00582. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.5527G>C	p.Asp1843His	missense_variant	40/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.5527G>C	p.Asp1843His	missense_variant	40/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.4876G>C	p.Asp1626His	missense_variant	38/91	2		A2
DNAH8	ENST00000449981.6	c.5527G>C	p.Asp1843His	missense_variant	39/82	5

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00645

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: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000518 AC: 130 AN: 251050 Hom.: 1 AF XY: 0.000361 AC XY: 49 AN XY: 135662

Gnomad AFR exome AF: 0.00745

Gnomad AMR exome AF: 0.000231

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1461518 Hom.: 0 Cov.: 31 AF XY: 0.000142 AC XY: 103 AN XY: 727080

Gnomad4 AFR exome AF: 0.00610

Gnomad4 AMR exome AF: 0.000358

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: 0.00000180

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74468

Gnomad4 AFR AF: 0.00645

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: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000272 Hom.: 0

Bravo AF: 0.00213

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000651 AC: 79

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

DNAH8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2020

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	Pathogenic	0.92
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.082	T;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
REVEL	Uncertain	0.44
Polyphen		1.0	.;.;D
Vest4		0.74
MVP		0.92
MPC		0.63
ClinPred		0.074	T
GERP RS		4.9
Varity_R		0.63
gMVP		0.63

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: rs61758415; hg19: chr6-38820530;