rs78849281

chr6-39012311-C-T

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.13468C>T(p.Arg4490Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,612,844 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4490H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (91 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.40

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=0.0075264275).
• BP6: Variant 6-39012311-C-T is Benign according to our data. Variant chr6-39012311-C-T is described in ClinVar as [Benign]. Clinvar id is 238637.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0016 (244/152252) while in subpopulation SAS AF= 0.0294 (142/4822). AF 95% confidence interval is 0.0255. There are 9 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.13468C>T	p.Arg4490Cys	missense_variant	90/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.13468C>T	p.Arg4490Cys	missense_variant	90/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.12817C>T	p.Arg4273Cys	missense_variant	88/91	2		A2

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152134 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00431 AC: 1083 AN: 251198 Hom.: 17 AF XY: 0.00529 AC XY: 718 AN XY: 135734

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0107

Gnomad SAS exome AF: 0.0279

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00276 AC: 4028 AN: 1460592 Hom.: 91 Cov.: 31 AF XY: 0.00349 AC XY: 2538 AN XY: 726510

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0339

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152252 Hom.: 9 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74454

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.0294

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000656 Hom.: 1

Bravo AF: 0.000752

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00503 AC: 611

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
REVEL	Uncertain	0.41
Polyphen		1.0	.;D
Vest4		0.81
MVP		0.62
MPC		0.67
ClinPred		0.14	T
GERP RS		5.3
Varity_R		0.79
gMVP		0.76

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: rs78849281; hg19: chr6-38980087; COSMIC: COSV59433187;