chr6-38737092-C-A

Variant names:

• chr6-38737092-C-A
• rs145115573
• NM_001206927.2:c.788C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001206927.2(DNAH8):​c.788C>A​(p.Ala263Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,563,160 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A263T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.90
• Publications: 8 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: ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023275465).
• BP6: Variant 6-38737092-C-A is Benign according to our data. Variant chr6-38737092-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 414396.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000289 (44/152186) while in subpopulation EAS AF = 0.00733 (38/5184). AF 95% confidence interval is 0.00549. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.788C>A	p.Ala263Glu	missense	Exon 6 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.137C>A	p.Ala46Glu	missense	Exon 5 of 92	NP_001362.2	Q96JB1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.788C>A	p.Ala263Glu	missense	Exon 6 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.137C>A	p.Ala46Glu	missense	Exon 4 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.788C>A	p.Ala263Glu	missense	Exon 5 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00731

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000599 AC: 127 AN: 212044 AF XY: 0.000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00796

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000273 AC: 385 AN: 1410974 Hom.: 0 Cov.: 30 AF XY: 0.000287 AC XY: 201 AN XY: 700974

African (AFR) AF: 0.00 AC: 0 AN: 30590

American (AMR) AF: 0.00 AC: 0 AN: 32814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24726

East Asian (EAS) AF: 0.00859 AC: 318 AN: 37002

South Asian (SAS) AF: 0.000461 AC: 35 AN: 75888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52762

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5642

European-Non Finnish (NFE) AF: 0.0000137 AC: 15 AN: 1093138

Other (OTH) AF: 0.000274 AC: 16 AN: 58412

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41518

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00733 AC: 38 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000485 Hom.: 0

Bravo AF: 0.000317

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.23
Sift	Benign	0.12	T
Polyphen		0.84	P
Vest4		0.75
MVP		0.83
MPC		0.27
ClinPred		0.11	T
GERP RS		4.3
Varity_R		0.36
gMVP		0.76
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs145115573; hg19: chr6-38704868;