rs75954496

chr6-38931867-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001206927.2(DNAH8):c.11331T>A(p.Thr3777=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,610,798 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 31)
  • Exomes 𝑓: 0.012 (182 hom.)
• Consequence: DNAH8 NM_001206927.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.318

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-38931867-T-A is Benign according to our data. Variant chr6-38931867-T-A is described in ClinVar as [Benign]. Clinvar id is 414412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.318 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0109 (1655/152214) while in subpopulation SAS AF= 0.0401 (193/4818). AF 95% confidence interval is 0.0354. There are 24 homozygotes in gnomad4. There are 882 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.11331T>A	p.Thr3777=	synonymous_variant	76/93	ENST00000327475.11
DNAH8-AS1	NR_038401.1	n.160+4426A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.11331T>A	p.Thr3777=	synonymous_variant	76/93	5	NM_001206927.2	P2
DNAH8-AS1	ENST00000416948.1	n.152+4426A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1648 AN: 152096 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0394

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00935

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.0142 AC: 3531 AN: 248108 Hom.: 54 AF XY: 0.0154 AC XY: 2067 AN XY: 134144

Gnomad AFR exome AF: 0.00484

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.0257

Gnomad SAS exome AF: 0.0338

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0121 AC: 17643 AN: 1458584 Hom.: 182 Cov.: 29 AF XY: 0.0127 AC XY: 9240 AN XY: 725650

Gnomad4 AFR exome AF: 0.00477

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.0289

Gnomad4 SAS exome AF: 0.0327

Gnomad4 FIN exome AF: 0.00199

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0109 AC: 1655 AN: 152214 Hom.: 24 Cov.: 31 AF XY: 0.0119 AC XY: 882 AN XY: 74418

Gnomad4 AFR AF: 0.00467

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.0259

Gnomad4 SAS AF: 0.0401

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00935

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0112 Hom.: 4

Bravo AF: 0.0110

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.0130

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNAH8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.41
Dann	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs75954496; hg19: chr6-38899643; COSMIC: COSV59433395; COSMIC: COSV59433395;