chr6-38828180-G-T

Variant names:

• chr6-38828180-G-T
• rs61748602
• NM_001206927.2:c.4084-4G>T

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.4084-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,575,248 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0063 (49 hom.)
• Consequence: DNAH8 NM_001206927.2 splice_region, intron
• Scores: Splicing: ADA: 0.0002234
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.436
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-38828180-G-T is Benign according to our data. Variant chr6-38828180-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00526 (801/152190) while in subpopulation NFE AF = 0.00697 (474/67972). AF 95% confidence interval is 0.00645. There are 2 homozygotes in GnomAd4. There are 403 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4084-4G>T		splice_region intron	N/A	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.3433-4G>T		splice_region intron	N/A	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.4084-4G>T		splice_region intron	N/A	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.3433-4G>T		splice_region intron	N/A	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.4084-4G>T		splice_region intron	N/A	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 801 AN: 152072 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00611 AC: 1403 AN: 229690 AF XY: 0.00621

Gnomad AFR exome AF: 0.000791

Gnomad AMR exome AF: 0.00314

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.00665

Gnomad OTH exome AF: 0.00797

GnomAD4 exome AF: 0.00634 AC: 9026 AN: 1423058 Hom.: 49 Cov.: 27 AF XY: 0.00634 AC XY: 4485 AN XY: 707444

African (AFR) AF: 0.000345 AC: 11 AN: 31918

American (AMR) AF: 0.00330 AC: 130 AN: 39382

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 461 AN: 25668

East Asian (EAS) AF: 0.00 AC: 0 AN: 38476

South Asian (SAS) AF: 0.00189 AC: 148 AN: 78414

European-Finnish (FIN) AF: 0.0155 AC: 822 AN: 53098

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5722

European-Non Finnish (NFE) AF: 0.00642 AC: 7002 AN: 1091266

Other (OTH) AF: 0.00753 AC: 445 AN: 59114

GnomAD4 genome AF: 0.00526 AC: 801 AN: 152190 Hom.: 2 Cov.: 31 AF XY: 0.00542 AC XY: 403 AN XY: 74394

African (AFR) AF: 0.00101 AC: 42 AN: 41548

American (AMR) AF: 0.00425 AC: 65 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3468

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

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.0123 AC: 130 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00697 AC: 474 AN: 67972

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00656 Hom.: 3

Bravo AF: 0.00478

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.47
PhyloP100		-0.44
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 27

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

Other links and lift over

dbSNP: rs61748602; hg19: chr6-38795956;