rs144711161

chr6-38899907-G-A

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_001206927.2(DNAH8):c.9194+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,568,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.93

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 Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 6-38899907-G-A is Pathogenic according to our data. Variant chr6-38899907-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 238657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.9194+1G>A		splice_donor_variant		ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.9194+1G>A		splice_donor_variant		5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.8543+1G>A		splice_donor_variant		2		A2
DNAH8	ENST00000449981.6	c.9194+1G>A		splice_donor_variant		5

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152006 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000838 AC: 18 AN: 214762 Hom.: 0 AF XY: 0.0000772 AC XY: 9 AN XY: 116518

Gnomad AFR exome AF: 0.0000661

Gnomad AMR exome AF: 0.000120

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: 0.000138

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 162 AN: 1416020 Hom.: 0 Cov.: 29 AF XY: 0.000125 AC XY: 88 AN XY: 701504

Gnomad4 AFR exome AF: 0.0000321

Gnomad4 AMR exome AF: 0.0000576

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: 0.000138

Gnomad4 OTH exome AF: 0.000137

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74360

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNAH8-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2023

The DNAH8 c.9194+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in literature. This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-38867683-G-A). However, loss-of-function variants have been reported to be causative for DNAH8-related disorders (for example, Watson et al. 2014. PubMed ID: 24307375; Liu et al. 2020. PubMed ID: 32619401; Yang et al. 2020. PubMed ID: 32681648; Zhou et al. 2021. PubMed ID: 33611675). In ClinVar, the c.9194+1G>A variant is interpreted as likely pathogenic (ClinVar ID: 239924). Based on these observations, this variant is classified as likely pathogenic. -

Primary ciliary dyskinesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

This sequence change affects a donor splice site in intron 62 of the DNAH8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAH8 are known to be pathogenic (PMID: 24307375, 32619401, 32681648). This variant is present in population databases (rs144711161, gnomAD 0.01%). 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: 238657). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144711161; hg19: chr6-38867683;