6-38832433-T-C

Position:

• chr6-38832433-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 402764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-38832433-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.4300T>C	p.Leu1434Leu	splice_region_variant, synonymous_variant	31/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.4300T>C	p.Leu1434Leu	splice_region_variant, synonymous_variant	31/93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.3649T>C	p.Leu1217Leu	splice_region_variant, synonymous_variant	29/91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.4300T>C	p.Leu1434Leu	splice_region_variant, synonymous_variant	30/82	5		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

GnomAD3 exomes AF: 0.180 AC: 45028 AN: 249740 Hom.: 4710 AF XY: 0.174 AC XY: 23517 AN XY: 134978

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 SAS exome AF: 0.201

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

Gnomad4 AFR exome AF: 0.372

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.157

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

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.0975

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.197

Alfa AF: 0.150 Hom.: 3675

Bravo AF: 0.225

Asia WGS AF: 0.234 AC: 814 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.136

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.32
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1678729; hg19: chr6-38800209; COSMIC: COSV59425769;