rs61757621

Positions:

• chr6-38781288-C-G

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.2174C>G​(p.Ala725Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,613,844 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.13

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016131371).
• BP6: Variant 6-38781288-C-G is Benign according to our data. Variant chr6-38781288-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 407294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (249/152216) while in subpopulation NFE AF= 0.00315 (214/68010). AF 95% confidence interval is 0.0028. There are 1 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.2174C>G	p.Ala725Gly	missense_variant	16/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.2174C>G	p.Ala725Gly	missense_variant	16/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.1523C>G	p.Ala508Gly	missense_variant	14/91	2		A2
DNAH8	ENST00000449981.6	c.2174C>G	p.Ala725Gly	missense_variant	15/82	5

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00129 AC: 323 AN: 251220 Hom.: 0 AF XY: 0.00133 AC XY: 181 AN XY: 135764

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00270 AC: 3941 AN: 1461628 Hom.: 8 Cov.: 31 AF XY: 0.00259 AC XY: 1883 AN XY: 727122

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00342

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00164 AC: 249 AN: 152216 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74422

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00155

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00131 AC: 159

EpiCase AF: 0.00229

EpiControl AF: 0.00296

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Apr 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

DNAH8: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	.;N;N
REVEL	Benign	0.12
Sift	Benign	0.13	.;T;T
Polyphen		0.0050	.;.;B
Vest4		0.40
MVP		0.65
MPC		0.13
ClinPred		0.020	T
GERP RS		5.6
Varity_R		0.27
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61757621; hg19: chr6-38749064;