6-38875744-C-T

Position:

• chr6-38875744-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001206927.2(DNAH8):​c.7774C>T​(p.Arg2592Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,852 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.793

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000637 (97/152166) while in subpopulation NFE AF= 0.00112 (76/68008). AF 95% confidence interval is 0.000915. There are 1 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.7774C>T	p.Arg2592Trp	missense_variant	53/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.7774C>T	p.Arg2592Trp	missense_variant	53/93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.7123C>T	p.Arg2375Trp	missense_variant	51/91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.7774C>T	p.Arg2592Trp	missense_variant	52/82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000502 AC: 126 AN: 251198 Hom.: 0 AF XY: 0.000457 AC XY: 62 AN XY: 135760

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00125 AC: 1833 AN: 1461686 Hom.: 2 Cov.: 32 AF XY: 0.00118 AC XY: 856 AN XY: 727144

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74406

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.000650

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 01, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2592 of the DNAH8 protein (p.Arg2592Trp). This variant is present in population databases (rs113332942, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 407296). 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) performed at Invitae indicates that this missense variant is expected to disrupt DNAH8 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	May 08, 2019	- -

Spermatogenic failure 46 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Oct 26, 2023	The DNAH8 c.7774C>T (p.Arg2592Trp) variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by three submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.096% in European (non-Finnish) population. Computational predictors suggest that the variant does not impact DNAH8 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 30, 2022	- -

DNAH8-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

The DNAH8 c.7774C>T variant is predicted to result in the amino acid substitution p.Arg2592Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.096% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.9	.;.;M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.0	.;D;D
REVEL	Benign	0.26
Sift	Benign	0.099	.;T;T
Polyphen		1.0	.;.;D
Vest4		0.81
MVP		0.69
MPC		0.13
ClinPred		0.11	T
GERP RS		0.21
Varity_R		0.28
gMVP		0.71

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: rs113332942; hg19: chr6-38843520;