6-39012224-C-T

Position:

• chr6-39012224-C-T

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.13381C>T​(p.Arg4461Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,602,132 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.88

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]

DNAH8 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012955099).
• BP6: Variant 6-39012224-C-T is Benign according to our data. Variant chr6-39012224-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 414397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00198 (301/152218) while in subpopulation NFE AF= 0.00315 (214/68010). AF 95% confidence interval is 0.0028. There are 1 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.13381C>T	p.Arg4461Cys	missense_variant	90/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.13381C>T	p.Arg4461Cys	missense_variant	90/93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.12730C>T	p.Arg4244Cys	missense_variant	88/91	2		ENSP00000352312.3

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152100 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00180 AC: 444 AN: 246350 Hom.: 1 AF XY: 0.00182 AC XY: 242 AN XY: 133170

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00433

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00315 AC: 4562 AN: 1449914 Hom.: 10 Cov.: 30 AF XY: 0.00310 AC XY: 2232 AN XY: 720074

Gnomad4 AFR exome AF: 0.000482

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00411

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00380

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152218 Hom.: 1 Cov.: 33 AF XY: 0.00179 AC XY: 133 AN XY: 74440

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00289 Hom.: 1

Bravo AF: 0.00182

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00156 AC: 189

EpiCase AF: 0.00268

EpiControl AF: 0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Nov 07, 2017	- -

DNAH8-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2022

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.9	.;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.018	.;D
Polyphen		1.0	.;D
Vest4		0.47
MVP		0.69
MPC		0.65
ClinPred		0.10	T
GERP RS		6.2
Varity_R		0.41
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143714496; hg19: chr6-38980000;