chr6-38973702-A-C

Variant names:

• chr6-38973702-A-C
• rs61757618
• NM_001206927.2:c.12567A>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001206927.2(DNAH8):​c.12567A>C​(p.Glu4189Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00053 in 1,607,608 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.703

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011534929).
• BP6: Variant 6-38973702-A-C is Benign according to our data. Variant chr6-38973702-A-C is described in ClinVar as [Benign]. Clinvar id is 414390.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00296 (451/152326) while in subpopulation AFR AF= 0.0104 (432/41570). AF 95% confidence interval is 0.00958. There are 2 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.12567A>C	p.Glu4189Asp	missense_variant	Exon 84 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.12567A>C	p.Glu4189Asp	missense_variant	Exon 84 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.11916A>C	p.Glu3972Asp	missense_variant	Exon 82 of 91	2		ENSP00000352312.3

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000829 AC: 202 AN: 243680 Hom.: 3 AF XY: 0.000523 AC XY: 69 AN XY: 131834

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000307

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: 0.0000269

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000276 AC: 401 AN: 1455282 Hom.: 1 Cov.: 30 AF XY: 0.000218 AC XY: 158 AN XY: 723772

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.000438

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: 0.00000451

Gnomad4 OTH exome AF: 0.000482

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74484

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000574 Hom.: 1

Bravo AF: 0.00351

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00106 AC: 129

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DNAH8-related disorder Benign:1

Jan 27, 2020

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.28
DEOGEN2	Benign	0.0051	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.0	.;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.6	.;N
REVEL	Benign	0.13
Sift	Benign	1.0	.;T
Polyphen		0.0	.;B
Vest4		0.27
MutPred		0.56		.;Loss of solvent accessibility (P = 0.0703);
MVP		0.19
MPC		0.11
ClinPred		0.0068	T
GERP RS		-1.4
Varity_R		0.075
gMVP		0.28

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: rs61757618; hg19: chr6-38941478;