rs61748601

Positions:

• chr6-38778400-G-A
• chr6-38778400-G-T

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.1975G>A​(p.Ala659Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,550,288 control chromosomes in the GnomAD database, including 16,848 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1395 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15453 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.719

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=0.0015652776).
• BP6: Variant 6-38778400-G-A is Benign according to our data. Variant chr6-38778400-G-A is described in ClinVar as [Benign]. Clinvar id is 402761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.1975G>A	p.Ala659Thr	missense_variant	14/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.1975G>A	p.Ala659Thr	missense_variant	14/93	5	NM_001206927.2	ENSP00000333363	P2
DNAH8	ENST00000359357.7	c.1324G>A	p.Ala442Thr	missense_variant	12/91	2		ENSP00000352312	A2
DNAH8	ENST00000449981.6	c.1975G>A	p.Ala659Thr	missense_variant	13/82	5		ENSP00000415331

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18608 AN: 152002 Hom.: 1385 Cov.: 32

Gnomad AFR AF: 0.0624

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0515

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.134 AC: 32702 AN: 243978 Hom.: 2908 AF XY: 0.128 AC XY: 16848 AN XY: 132136

Gnomad AFR exome AF: 0.0607

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0107

Gnomad SAS exome AF: 0.0528

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.140 AC: 195835 AN: 1398168 Hom.: 15453 Cov.: 24 AF XY: 0.137 AC XY: 95682 AN XY: 698356

Gnomad4 AFR exome AF: 0.0590

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.0153

Gnomad4 SAS exome AF: 0.0522

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.123 AC: 18652 AN: 152120 Hom.: 1395 Cov.: 32 AF XY: 0.121 AC XY: 8986 AN XY: 74338

Gnomad4 AFR AF: 0.0629

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0154

Gnomad4 SAS AF: 0.0507

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.153

Gnomad4 OTH AF: 0.118

Alfa AF: 0.139 Hom.: 2680

Bravo AF: 0.128

TwinsUK AF: 0.149 AC: 553

ALSPAC AF: 0.161 AC: 620

ESP6500AA AF: 0.0651 AC: 287

ESP6500EA AF: 0.152 AC: 1305

ExAC AF: 0.128 AC: 15532

Asia WGS AF: 0.0790 AC: 277 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	0.067
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.62
DEOGEN2	Benign	0.0077	T;T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.18	.;.;N
MutationTaster	Benign	0.056	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.48	.;N;N
REVEL	Benign	0.093
Sift	Benign	0.71	.;T;T
Polyphen		0.0	.;.;B
Vest4		0.094
MPC		0.12
ClinPred		0.0011	T
GERP RS		3.5
Varity_R		0.051
gMVP		0.14

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: rs61748601; hg19: chr6-38746176;