rs185283741

Positions:

• chr6-38935602-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001206927.2(DNAH8):​c.11468C>T​(p.Ala3823Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,611,272 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (2 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.83

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-AS1 (HGNC:40188): (DNAH8 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07509413).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000608 (887/1459166) while in subpopulation NFE AF= 0.000739 (821/1110808). AF 95% confidence interval is 0.000696. There are 2 homozygotes in gnomad4_exome. There are 395 alleles in male gnomad4_exome subpopulation. Median coverage is 29. 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	UniProt
DNAH8	NM_001206927.2	c.11468C>T	p.Ala3823Val	missense_variant	77/93	ENST00000327475.11
DNAH8-AS1	NR_038401.1	n.160+691G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.11468C>T	p.Ala3823Val	missense_variant	77/93	5	NM_001206927.2	P2
DNAH8-AS1	ENST00000416948.1	n.152+691G>A		intron_variant, non_coding_transcript_variant		2
DNAH8	ENST00000359357.7	c.10817C>T	p.Ala3606Val	missense_variant	75/91	2		A2
DNAH8	ENST00000449981.6	c.11468C>T	p.Ala3823Val	missense_variant	76/82	5

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000373 AC: 93 AN: 249318 Hom.: 1 AF XY: 0.000319 AC XY: 43 AN XY: 134812

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000614

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000513

Gnomad NFE exome AF: 0.000495

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000608 AC: 887 AN: 1459166 Hom.: 2 Cov.: 29 AF XY: 0.000544 AC XY: 395 AN XY: 725864

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000540

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000282

Gnomad4 NFE exome AF: 0.000739

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74348

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000437 AC: 53

EpiCase AF: 0.000437

EpiControl AF: 0.000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Feb 03, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 05, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3823 of the DNAH8 protein (p.Ala3823Val). This variant is present in population databases (rs185283741, 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: 569635). 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: "Tolerated"; 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.11468C>T (p.A3823V) alteration is located in exon 77 (coding exon 76) of the DNAH8 gene. This alteration results from a C to T substitution at nucleotide position 11468, causing the alanine (A) at amino acid position 3823 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Spermatogenic failure 46 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Jan 19, 2021

This DNAH8 variant (rs185283741) is present in a large population dataset (gnomAD: 102/280708 total alleles; 0.036%; no homozygotes) and has been reported in ClinVar. It has not been reported in the literature, to our knowledge. One bioinformatic tool queried predicts that this substitution would be tolerated, and the alanine residue at this position is poorly evolutionarily conserved across the species assessed. We consider the clinical significance of c.11432C>T to be uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.55	T
REVEL	Benign	0.097
Polyphen		0.0070	.;.;B
Vest4		0.42
MVP		0.53
MPC		0.17
ClinPred		0.061	T
GERP RS		6.0
Varity_R		0.16
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs185283741; hg19: chr6-38903378;