6-39012305-A-G

Position:

• chr6-39012305-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206927.2(DNAH8):​c.13462A>G​(p.Ile4488Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,611,998 control chromosomes in the GnomAD database, including 20,859 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1833 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19026 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.232

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=0.0017467737).
• BP6: Variant 6-39012305-A-G is Benign according to our data. Variant chr6-39012305-A-G is described in ClinVar as [Benign]. Clinvar id is 257630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.13462A>G	p.Ile4488Val	missense_variant	90/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.13462A>G	p.Ile4488Val	missense_variant	90/93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.12811A>G	p.Ile4271Val	missense_variant	88/91	2		ENSP00000352312.3

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22541 AN: 152148 Hom.: 1834 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.143 AC: 35830 AN: 250908 Hom.: 3018 AF XY: 0.146 AC XY: 19837 AN XY: 135584

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.00310

Gnomad SAS exome AF: 0.135

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.156 AC: 227704 AN: 1459732 Hom.: 19026 Cov.: 31 AF XY: 0.156 AC XY: 113371 AN XY: 726130

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.265

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.159

GnomAD4 genome AF: 0.148 AC: 22537 AN: 152266 Hom.: 1833 Cov.: 32 AF XY: 0.144 AC XY: 10711 AN XY: 74466

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.282

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.0960

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.171

Alfa AF: 0.164 Hom.: 4878

Bravo AF: 0.154

TwinsUK AF: 0.158 AC: 585

ALSPAC AF: 0.170 AC: 655

ESP6500AA AF: 0.146 AC: 642

ESP6500EA AF: 0.180 AC: 1549

ExAC AF: 0.146 AC: 17690

Asia WGS AF: 0.0600 AC: 210 AN: 3478

EpiCase AF: 0.176

EpiControl AF: 0.172

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.9
DANN	Benign	0.94
DEOGEN2	Benign	0.0023	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.42	.;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.037
Sift	Benign	0.15	T;T
Polyphen		0.0	.;B
Vest4		0.045
MPC		0.10
ClinPred		0.0015	T
GERP RS		2.5
Varity_R		0.056
gMVP		0.21

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: rs10484847; hg19: chr6-38980081; COSMIC: COSV59446520;