rs142328376

chr6-38886870-T-C

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.8339T>C(p.Ile2780Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00551 in 1,614,082 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2780V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (37 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.17

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=0.048991323).
• BP6: Variant 6-38886870-T-C is Benign according to our data. Variant chr6-38886870-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 224919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00455 (693/152334) while in subpopulation AMR AF= 0.0109 (167/15302). AF 95% confidence interval is 0.00956. There are 4 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.8339T>C	p.Ile2780Thr	missense_variant	57/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.8339T>C	p.Ile2780Thr	missense_variant	57/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.7688T>C	p.Ile2563Thr	missense_variant	55/91	2		A2
DNAH8	ENST00000449981.6	c.8339T>C	p.Ile2780Thr	missense_variant	56/82	5

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152216 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00454 AC: 1140 AN: 251146 Hom.: 3 AF XY: 0.00475 AC XY: 645 AN XY: 135718

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000831

Gnomad NFE exome AF: 0.00700

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00562 AC: 8208 AN: 1461748 Hom.: 37 Cov.: 31 AF XY: 0.00550 AC XY: 4001 AN XY: 727182

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00599

Gnomad4 ASJ exome AF: 0.00666

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00658

Gnomad4 OTH exome AF: 0.00512

GnomAD4 genome AF: 0.00455 AC: 693 AN: 152334 Hom.: 4 Cov.: 32 AF XY: 0.00405 AC XY: 302 AN XY: 74478

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00631

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00584 Hom.: 6

Bravo AF: 0.00493

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00437 AC: 531

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00671

EpiControl AF: 0.00729

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

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

Nov 01, 2023

DNAH8: BS2 -

Spermatogenic failure 46 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Uncertain	0.076	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
REVEL	Uncertain	0.53
Polyphen		1.0	.;.;D
Vest4		0.91
MVP		0.83
MPC		0.51
ClinPred		0.049	T
GERP RS		5.8
Varity_R		0.77
gMVP		0.82

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: rs142328376; hg19: chr6-38854646;