rs145365277

Variant names:

• chr6-38883366-G-A
• rs145365277
• NM_001206927.2:c.8046G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001206927.2(DNAH8):​c.8046G>A​(p.Met2682Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,613,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08624184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.8046G>A	p.Met2682Ile	missense_variant	Exon 55 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.8046G>A	p.Met2682Ile	missense_variant	Exon 55 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.7395G>A	p.Met2465Ile	missense_variant	Exon 53 of 91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.8046G>A	p.Met2682Ile	missense_variant	Exon 54 of 82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000798 AC: 20 AN: 250554 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135438

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000261 AC: 381 AN: 1460874 Hom.: 0 Cov.: 31 AF XY: 0.000253 AC XY: 184 AN XY: 726762

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with isoleucine at codon 2682 of the DNAH8 protein (p.Met2682Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs145365277, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 407291). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.025	T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	.;.;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	.;N;N
REVEL	Benign	0.18
Sift	Benign	0.54	.;T;T
Polyphen		0.033	.;.;B
Vest4		0.88
MutPred		0.61		.;.;Gain of ubiquitination at K2467 (P = 0.0683);
MVP		0.39
MPC		0.18
ClinPred		0.052	T
GERP RS		5.2
Varity_R		0.35
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145365277; hg19: chr6-38851142;