6-38832433-T-C

Variant names:

• chr6-38832433-T-C
• rs1678729
• NM_001206927.2:c.4300T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001206927.2(DNAH8):​c.4300T>C​(p.Leu1434Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,558,752 control chromosomes in the GnomAD database, including 22,506 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4275 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18231 hom.)
• Consequence: DNAH8 NM_001206927.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001586
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0940
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-38832433-T-C is Benign according to our data. Variant chr6-38832433-T-C is described in ClinVar as Benign. ClinVar VariationId is 402764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.094 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.4300T>C	p.Leu1434Leu	splice_region synonymous	Exon 31 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.3649T>C	p.Leu1217Leu	splice_region synonymous	Exon 30 of 92	NP_001362.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.4300T>C	p.Leu1434Leu	splice_region synonymous	Exon 31 of 93	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.3649T>C	p.Leu1217Leu	splice_region synonymous	Exon 29 of 91	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.4300T>C	p.Leu1434Leu	splice_region synonymous	Exon 30 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32149 AN: 151992 Hom.: 4259 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.0975

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.180 AC: 45028 AN: 249740 AF XY: 0.174

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.151 AC: 212869 AN: 1406642 Hom.: 18231 Cov.: 24 AF XY: 0.151 AC XY: 106525 AN XY: 703262

African (AFR) AF: 0.372 AC: 11886 AN: 31962

American (AMR) AF: 0.198 AC: 8787 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2765 AN: 25784

East Asian (EAS) AF: 0.318 AC: 12483 AN: 39248

South Asian (SAS) AF: 0.200 AC: 16975 AN: 84928

European-Finnish (FIN) AF: 0.142 AC: 7589 AN: 53362

Middle Eastern (MID) AF: 0.131 AC: 738 AN: 5650

European-Non Finnish (NFE) AF: 0.134 AC: 142455 AN: 1062788

Other (OTH) AF: 0.157 AC: 9191 AN: 58468

GnomAD4 genome AF: 0.212 AC: 32194 AN: 152110 Hom.: 4275 Cov.: 32 AF XY: 0.210 AC XY: 15645 AN XY: 74372

African (AFR) AF: 0.366 AC: 15177 AN: 41458

American (AMR) AF: 0.182 AC: 2780 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 338 AN: 3466

East Asian (EAS) AF: 0.286 AC: 1478 AN: 5172

South Asian (SAS) AF: 0.199 AC: 957 AN: 4812

European-Finnish (FIN) AF: 0.144 AC: 1522 AN: 10590

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9260 AN: 68004

Other (OTH) AF: 0.197 AC: 417 AN: 2112

Alfa AF: 0.165 Hom.: 6429

Bravo AF: 0.225

Asia WGS AF: 0.234 AC: 814 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.136

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.32
DANN	Benign	0.65
PhyloP100		-0.094
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs1678729; hg19: chr6-38800209; COSMIC: COSV59425769;