rs142863013

chr6-38734588-G-Achr6-38734588-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001206927.2(DNAH8):c.725G>A(p.Arg242His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,613,482 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0670

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009264529).
• BP6: Variant 6-38734588-G-A is Benign according to our data. Variant chr6-38734588-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238655.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152274) while in subpopulation EAS AF= 0.00308 (16/5188). AF 95% confidence interval is 0.00193. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.725G>A	p.Arg242His	missense_variant	5/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.725G>A	p.Arg242His	missense_variant	5/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.74G>A	p.Arg25His	missense_variant	3/91	2		A2
DNAH8	ENST00000449981.6	c.725G>A	p.Arg242His	missense_variant	4/82	5

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000438 AC: 110 AN: 251274 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135790

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00370

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000296 AC: 432 AN: 1461208 Hom.: 1 Cov.: 32 AF XY: 0.000279 AC XY: 203 AN XY: 726914

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00255

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000227

Gnomad4 OTH exome AF: 0.000895

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74462

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000399 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Spermatogenic failure 46 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.012	T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.25	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
REVEL	Benign	0.095
Polyphen		0.66	.;.;P
Vest4		0.18
MVP		0.64
MPC		0.15
ClinPred		0.0098	T
GERP RS		-1.7
Varity_R		0.047
gMVP		0.26

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: rs142863013; hg19: chr6-38702364; COSMIC: COSV59458773; COSMIC: COSV59458773;