rs141012833

Variant names:

• chr6-38842858-A-T
• rs141012833
• NM_001206927.2:c.4800A>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.4800A>T​(p.Arg1600Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.825

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=0.035380036).
• BP6: Variant 6-38842858-A-T is Benign according to our data. Variant chr6-38842858-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 579789.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000545 (83/152276) while in subpopulation AFR AF= 0.00176 (73/41558). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.4800A>T	p.Arg1600Ser	missense_variant	Exon 35 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.4800A>T	p.Arg1600Ser	missense_variant	Exon 35 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.4149A>T	p.Arg1383Ser	missense_variant	Exon 33 of 91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.4800A>T	p.Arg1600Ser	missense_variant	Exon 34 of 82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251060 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135674

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461560 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727100

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74450

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000623

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH8: PM2:Supporting, BP4 -

Primary ciliary dyskinesia Benign:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	.;.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	.;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.078	.;T;T
Polyphen		0.93	.;.;P
Vest4		0.65
MutPred		0.51		.;.;Loss of solvent accessibility (P = 0.1362);
MVP		0.61
MPC		0.36
ClinPred		0.17	T
GERP RS		2.7
Varity_R		0.49
gMVP		0.54

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: rs141012833; hg19: chr6-38810634;