rs78877915

Variant names:

• chr6-38842667-C-A
• rs78877915
• NM_001206927.2:c.4609C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-38842667-C-A
• chr6-38842667-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001206927.2(DNAH8):​c.4609C>A​(p.Arg1537Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,414 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 0 publications found

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]

DNAH8 Gene-Disease associations (from GenCC):

• spermatogenic failure 46

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• spermatogenic failure 5

  Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.4609C>A	p.Arg1537Ser	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.4609C>A	p.Arg1537Ser	missense_variant	Exon 35 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.3958C>A	p.Arg1320Ser	missense_variant	Exon 33 of 91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.4609C>A	p.Arg1537Ser	missense_variant	Exon 34 of 82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457414 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724554

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 44014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110804

Other (OTH) AF: 0.00 AC: 0 AN: 60212

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T;T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.7	.;.;M
PhyloP100		4.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.3	.;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	.;D;D
Polyphen		1.0	.;.;D
Vest4		0.55
MutPred		0.65		.;.;Loss of MoRF binding (P = 0.0245);
MVP		0.84
MPC		0.59
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.57
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78877915; hg19: chr6-38810443;