rs138703233

Positions:

• chr6-38909677-C-A

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.9673C>A​(p.Gln3225Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000945 in 1,614,082 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (3 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18

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=0.020689428).
• BP6: Variant 6-38909677-C-A is Benign according to our data. Variant chr6-38909677-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 454610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000657 (100/152272) while in subpopulation SAS AF= 0.00145 (7/4818). AF 95% confidence interval is 0.000875. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.9673C>A	p.Gln3225Lys	missense_variant	65/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.9673C>A	p.Gln3225Lys	missense_variant	65/93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.9022C>A	p.Gln3008Lys	missense_variant	63/91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.9673C>A	p.Gln3225Lys	missense_variant	64/82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000892 AC: 224 AN: 251158 Hom.: 2 AF XY: 0.000958 AC XY: 130 AN XY: 135734

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000976 AC: 1426 AN: 1461810 Hom.: 3 Cov.: 31 AF XY: 0.00101 AC XY: 736 AN XY: 727220

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000927

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74460

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000688

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00160

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

DNAH8-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2023

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	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.36	.;.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	.;N;N
REVEL	Benign	0.072
Sift	Benign	0.14	.;T;T
Polyphen		0.0010	.;.;B
Vest4		0.47
MVP		0.54
MPC		0.16
ClinPred		0.024	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.52

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: rs138703233; hg19: chr6-38877453;