rs150571615

Variant names:

• chr6-38896194-C-T
• rs150571615
• NM_001206927.2:c.8909C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001206927.2(DNAH8):​c.8909C>T​(p.Ser2970Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,613,978 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.41
• Publications: 2 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032912493).
• BP6: Variant 6-38896194-C-T is Benign according to our data. Variant chr6-38896194-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414375.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00146 (223/152242) while in subpopulation AFR AF = 0.0052 (216/41540). AF 95% confidence interval is 0.00463. There are 3 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.8909C>T	p.Ser2970Phe	missense	Exon 60 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.8258C>T	p.Ser2753Phe	missense	Exon 59 of 92	NP_001362.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.8909C>T	p.Ser2970Phe	missense	Exon 60 of 93	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.8258C>T	p.Ser2753Phe	missense	Exon 58 of 91	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.8909C>T	p.Ser2970Phe	missense	Exon 59 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152124 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000339 AC: 85 AN: 250936 AF XY: 0.000192

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 105 AN XY: 727162

African (AFR) AF: 0.00565 AC: 189 AN: 33476

American (AMR) AF: 0.000559 AC: 25 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111932

Other (OTH) AF: 0.000497 AC: 30 AN: 60390

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152242 Hom.: 3 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74448

African (AFR) AF: 0.00520 AC: 216 AN: 41540

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000615 Hom.: 1

Bravo AF: 0.00161

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000395 AC: 48

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.47
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.40	N
PhyloP100		1.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.072
Sift	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.32
MPC		0.13
ClinPred		0.0060	T
GERP RS		1.1
Varity_R		0.057
gMVP		0.25
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs150571615; hg19: chr6-38863970;