chr6-38906336-A-G

Variant names:

• chr6-38906336-A-G
• rs139533720
• NM_001206927.2:c.9277A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001206927.2(DNAH8):​c.9277A>G​(p.Ile3093Val) variant causes a missense change. The variant allele was found at a frequency of 0.00022 in 1,611,270 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 6.10
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058484256).
• BP6: Variant 6-38906336-A-G is Benign according to our data. Variant chr6-38906336-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 525254.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000219 (320/1458928) while in subpopulation MID AF = 0.00355 (18/5072). AF 95% confidence interval is 0.00229. There are 1 homozygotes in GnomAdExome4. There are 166 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.9277A>G	p.Ile3093Val	missense	Exon 63 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.8626A>G	p.Ile2876Val	missense	Exon 62 of 92	NP_001362.2
	DNAH8-AS1	NR_038401.1		n.*159T>C		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.9277A>G	p.Ile3093Val	missense	Exon 63 of 93	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.8626A>G	p.Ile2876Val	missense	Exon 61 of 91	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.9277A>G	p.Ile3093Val	missense	Exon 62 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000319 AC: 80 AN: 250736 AF XY: 0.000325

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000219 AC: 320 AN: 1458928 Hom.: 1 Cov.: 29 AF XY: 0.000229 AC XY: 166 AN XY: 725818

African (AFR) AF: 0.0000598 AC: 2 AN: 33422

American (AMR) AF: 0.000201 AC: 9 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39614

South Asian (SAS) AF: 0.000489 AC: 42 AN: 85924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00355 AC: 18 AN: 5072

European-Non Finnish (NFE) AF: 0.000141 AC: 157 AN: 1110556

Other (OTH) AF: 0.000332 AC: 20 AN: 60216

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000174 AC XY: 13 AN XY: 74500

African (AFR) AF: 0.0000962 AC: 4 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000444 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000255 AC: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9277A>G (p.I3093V) alteration is located in exon 63 (coding exon 62) of the DNAH8 gene. This alteration results from a A to G substitution at nucleotide position 9277, causing the isoleucine (I) at amino acid position 3093 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

not provided Uncertain:1

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia Benign:1

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH8-related disorder Benign:1

May 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.14
Sift	Uncertain	0.012	D
Polyphen		0.025	B
Vest4		0.34
MVP		0.59
MPC		0.12
ClinPred		0.059	T
GERP RS		4.6
Varity_R		0.20
gMVP		0.32
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs139533720; hg19: chr6-38874112;