rs140935840

chr6-38909578-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001206927.2(DNAH8):c.9574A>G(p.Met3192Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000387 in 1,614,116 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.40

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014436275).
• BP6: Variant 6-38909578-A-G is Benign according to our data. Variant chr6-38909578-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 414381.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 = 0.00192 (293/152282) while in subpopulation AFR AF= 0.0064 (266/41556). AF 95% confidence interval is 0.00577. There are 1 homozygotes in gnomad4. There are 150 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.9574A>G	p.Met3192Val	missense_variant	65/93	ENST00000327475.11
DNAH8-AS1	NR_038401.1	n.783-1741T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.9574A>G	p.Met3192Val	missense_variant	65/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.8923A>G	p.Met2975Val	missense_variant	63/91	2		A2
DNAH8	ENST00000449981.6	c.9574A>G	p.Met3192Val	missense_variant	64/82	5

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152164 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000486 AC: 122 AN: 251286 Hom.: 0 AF XY: 0.000412 AC XY: 56 AN XY: 135804

Gnomad AFR exome AF: 0.00572

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000227 AC: 332 AN: 1461834 Hom.: 1 Cov.: 31 AF XY: 0.000237 AC XY: 172 AN XY: 727222

Gnomad4 AFR exome AF: 0.00678

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152282 Hom.: 1 Cov.: 33 AF XY: 0.00201 AC XY: 150 AN XY: 74472

Gnomad4 AFR AF: 0.00640

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000312 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

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

Jan 25, 2024

- -

DNAH8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

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	Benign	0.092
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.071	T;T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
REVEL	Benign	0.25
Polyphen		0.20	.;.;B
Vest4		0.55
MVP		0.61
MPC		0.14
ClinPred		0.029	T
GERP RS		5.6
Varity_R		0.26
gMVP		0.55

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: rs140935840; hg19: chr6-38877354;