rs61757218

chr6-38938181-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001206927.2(DNAH8):c.11771C>T(p.Thr3924Met) variant causes a missense change. The variant allele was found at a frequency of 0.00617 in 1,613,926 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0061 (31 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3
• Conservation: PhyloP100: 6.16

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014879525).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00663 (1009/152274) while in subpopulation AFR AF= 0.00917 (381/41552). AF 95% confidence interval is 0.00841. There are 7 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.11771C>T	p.Thr3924Met	missense_variant	78/93	ENST00000327475.11
DNAH8-AS1	NR_038401.1	n.61-1789G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.11771C>T	p.Thr3924Met	missense_variant	78/93	5	NM_001206927.2	P2
DNAH8-AS1	ENST00000416948.1	n.53-1789G>A		intron_variant, non_coding_transcript_variant		2
DNAH8	ENST00000359357.7	c.11120C>T	p.Thr3707Met	missense_variant	76/91	2		A2
DNAH8	ENST00000449981.6	c.11771C>T	p.Thr3924Met	missense_variant	77/82	5

Frequencies

GnomAD3 genomes AF: 0.00663 AC: 1009 AN: 152156 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00922

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00832

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00661

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00518 AC: 1298 AN: 250738 Hom.: 4 AF XY: 0.00504 AC XY: 683 AN XY: 135550

Gnomad AFR exome AF: 0.00855

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.00159

Gnomad NFE exome AF: 0.00705

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00613 AC: 8956 AN: 1461652 Hom.: 31 Cov.: 34 AF XY: 0.00599 AC XY: 4352 AN XY: 727130

Gnomad4 AFR exome AF: 0.00998

Gnomad4 AMR exome AF: 0.00523

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00204

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.00681

Gnomad4 OTH exome AF: 0.00664

GnomAD4 genome AF: 0.00663 AC: 1009 AN: 152274 Hom.: 7 Cov.: 31 AF XY: 0.00653 AC XY: 486 AN XY: 74446

Gnomad4 AFR AF: 0.00917

Gnomad4 AMR AF: 0.00831

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00661

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00605 Hom.: 8

Bravo AF: 0.00707

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00510 AC: 619

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00699

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2023	Identified in the heterozygous state in a patient with transposition of the great arteries and abnormal ciliary motion (Zahid et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32619401, 29444099) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	DNAH8: BS2 -

Spermatogenic failure 46 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 13, 2020

- -

not specified Benign:1

Likely 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: Candidate PCD gene, but frequency is high -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Uncertain	0.075	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
REVEL	Uncertain	0.37
Polyphen		1.0	.;.;D
Vest4		0.79
MVP		0.87
MPC		0.58
ClinPred		0.084	T
GERP RS		5.6
Varity_R		0.64
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: rs61757218; hg19: chr6-38905957; COSMIC: COSV105236178;