rs45622336

Positions:

• chr6-38837977-G-A
• chr6-38837977-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001206927.2(DNAH8):​c.4401G>A​(p.Thr1467=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,612,986 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (54 hom.)
• Consequence: DNAH8 NM_001206927.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.69

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-38837977-G-A is Benign according to our data. Variant chr6-38837977-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00419 (638/152228) while in subpopulation NFE AF= 0.00776 (528/68004). AF 95% confidence interval is 0.00722. There are 6 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.4401G>A	p.Thr1467=	synonymous_variant	33/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.4401G>A	p.Thr1467=	synonymous_variant	33/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.3750G>A	p.Thr1250=	synonymous_variant	31/91	2		A2
DNAH8	ENST00000449981.6	c.4401G>A	p.Thr1467=	synonymous_variant	32/82	5

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 639 AN: 152110 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00776

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00452 AC: 1133 AN: 250666 Hom.: 4 AF XY: 0.00469 AC XY: 635 AN XY: 135504

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00174

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00805

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00705 AC: 10305 AN: 1460758 Hom.: 54 Cov.: 29 AF XY: 0.00691 AC XY: 5023 AN XY: 726736

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.00256

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.000993

Gnomad4 NFE exome AF: 0.00864

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00419 AC: 638 AN: 152228 Hom.: 6 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74428

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00161

Gnomad4 NFE AF: 0.00776

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00452 Hom.: 2

Bravo AF: 0.00429

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00808

EpiControl AF: 0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

DNAH8: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.27
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs45622336; hg19: chr6-38805753;