rs189023122

chr6-39008899-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_001206927.2(DNAH8):c.13300C>T(p.Arg4434Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,607,380 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R4434R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.811

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2807779).
• BP6: Variant 6-39008899-C-T is Benign according to our data. Variant chr6-39008899-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 454549.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.13300C>T	p.Arg4434Trp	missense_variant	89/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.13300C>T	p.Arg4434Trp	missense_variant	89/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.12649C>T	p.Arg4217Trp	missense_variant	87/91	2		A2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151966 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000298 AC: 75 AN: 251258 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000528 AC: 769 AN: 1455414 Hom.: 1 Cov.: 29 AF XY: 0.000504 AC XY: 365 AN XY: 724508

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000570

Gnomad4 OTH exome AF: 0.000648

GnomAD4 genome AF: 0.000296 AC: 45 AN: 151966 Hom.: 0 Cov.: 31 AF XY: 0.000337 AC XY: 25 AN XY: 74222

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000423 Hom.: 1

Bravo AF: 0.000321

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.59	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
REVEL	Uncertain	0.29
Polyphen		1.0	.;D
Vest4		0.85
MVP		0.60
MPC		0.59
ClinPred		0.38	T
GERP RS		4.8
Varity_R		0.84
gMVP		0.73

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: rs189023122; hg19: chr6-38976675;