rs61748600

Positions:

• chr6-38761735-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206927.2(DNAH8):​c.1549T>C​(p.Tyr517His) variant causes a missense change. The variant allele was found at a frequency of 0.141 in 1,558,360 control chromosomes in the GnomAD database, including 17,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1386 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16063 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.34

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002126515).
• BP6: Variant 6-38761735-T-C is Benign according to our data. Variant chr6-38761735-T-C is described in ClinVar as [Benign]. Clinvar id is 402760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-38761735-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.1549T>C	p.Tyr517His	missense_variant	11/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.1549T>C	p.Tyr517His	missense_variant	11/93	5	NM_001206927.2	ENSP00000333363	P2
DNAH8	ENST00000359357.7	c.898T>C	p.Tyr300His	missense_variant	9/91	2		ENSP00000352312	A2
DNAH8	ENST00000449981.6	c.1549T>C	p.Tyr517His	missense_variant	10/82	5		ENSP00000415331

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18497 AN: 152122 Hom.: 1376 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0510

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.130 AC: 27051 AN: 207336 Hom.: 2323 AF XY: 0.125 AC XY: 14163 AN XY: 113612

Gnomad AFR exome AF: 0.0568

Gnomad AMR exome AF: 0.268

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.0532

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.144 AC: 201814 AN: 1406120 Hom.: 16063 Cov.: 27 AF XY: 0.140 AC XY: 98181 AN XY: 699940

Gnomad4 AFR exome AF: 0.0564

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0157

Gnomad4 SAS exome AF: 0.0530

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.122 AC: 18529 AN: 152240 Hom.: 1386 Cov.: 32 AF XY: 0.120 AC XY: 8929 AN XY: 74430

Gnomad4 AFR AF: 0.0598

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0154

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.153

Gnomad4 OTH AF: 0.118

Alfa AF: 0.144 Hom.: 2859

Bravo AF: 0.127

TwinsUK AF: 0.149 AC: 554

ALSPAC AF: 0.162 AC: 623

ESP6500AA AF: 0.0633 AC: 279

ESP6500EA AF: 0.153 AC: 1313

ExAC AF: 0.128 AC: 15513

Asia WGS AF: 0.0770 AC: 270 AN: 3478

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
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	D;D;D
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	.;.;M
MutationTaster	Benign	0.0000039	P;P;P
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Benign	0.23
Sift	Benign	0.10	.;T;T
Polyphen		0.43	.;.;B
Vest4		0.30
MPC		0.44
ClinPred		0.029	T
GERP RS		6.0
Varity_R		0.49
gMVP		0.68

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: rs61748600; hg19: chr6-38729511; COSMIC: COSV59480744; COSMIC: COSV59480744;