rs78877915

Positions:

• chr6-38842667-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001206927.2(DNAH8):​c.4609C>T​(p.Arg1537Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,609,500 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1537L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0994817).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000158 (231/1457416) while in subpopulation EAS AF= 0.00341 (135/39612). AF 95% confidence interval is 0.00294. There are 0 homozygotes in gnomad4_exome. There are 128 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.4609C>T	p.Arg1537Cys	missense_variant	35/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.4609C>T	p.Arg1537Cys	missense_variant	35/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7	c.3958C>T	p.Arg1320Cys	missense_variant	33/91	2		A2
DNAH8	ENST00000449981.6	c.4609C>T	p.Arg1537Cys	missense_variant	34/82	5

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000162 AC: 40 AN: 246404 Hom.: 0 AF XY: 0.000203 AC XY: 27 AN XY: 133024

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000547

Gnomad SAS exome AF: 0.000279

Gnomad FIN exome AF: 0.000696

Gnomad NFE exome AF: 0.0000534

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 231 AN: 1457416 Hom.: 0 Cov.: 32 AF XY: 0.000177 AC XY: 128 AN XY: 724554

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00341

Gnomad4 SAS exome AF: 0.000178

Gnomad4 FIN exome AF: 0.000544

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74352

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000946

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000870 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1537 of the DNAH8 protein (p.Arg1537Cys). This variant is present in population databases (rs78877915, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 454573). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	4.1	.;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.1	.;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	.;D;D
Polyphen		1.0	.;.;D
Vest4		0.34
MVP		0.84
MPC		0.35
ClinPred		0.70	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs78877915; hg19: chr6-38810443; COSMIC: COSV59485699;