rs138703233

Variant names:

• chr6-38909677-C-A
• rs138703233
• NM_001206927.2:c.9673C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001206927.2(DNAH8):​c.9673C>A​(p.Gln3225Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000945 in 1,614,082 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (3 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18
• Publications: 4 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-AS1 (HGNC:40188): (DNAH8 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020689428).
• BP6: Variant 6-38909677-C-A is Benign according to our data. Variant chr6-38909677-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 454610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000657 (100/152272) while in subpopulation SAS AF = 0.00145 (7/4818). AF 95% confidence interval is 0.000875. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.9673C>A	p.Gln3225Lys	missense	Exon 65 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.9022C>A	p.Gln3008Lys	missense	Exon 64 of 92	NP_001362.2	Q96JB1-1
	DNAH8-AS1	NR_038401.1		n.783-1840G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.9673C>A	p.Gln3225Lys	missense	Exon 65 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.9022C>A	p.Gln3008Lys	missense	Exon 63 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.9673C>A	p.Gln3225Lys	missense	Exon 64 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000892 AC: 224 AN: 251158 AF XY: 0.000958

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000976 AC: 1426 AN: 1461810 Hom.: 3 Cov.: 31 AF XY: 0.00101 AC XY: 736 AN XY: 727220

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000927 AC: 80 AN: 86258

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53414

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00109 AC: 1211 AN: 1111958

Other (OTH) AF: 0.000944 AC: 57 AN: 60386

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74460

African (AFR) AF: 0.000192 AC: 8 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15286

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000688

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	DNAH8-related disorder (1)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.36	N
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.072
Sift	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.47
MVP		0.54
MPC		0.16
ClinPred		0.024	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.52
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs138703233; hg19: chr6-38877453;