rs138016358

Positions:

• chr6-38929574-C-G
• chr6-38929574-C-T

Variant summary

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

The NM_001206927.2(DNAH8):​c.11182C>G​(p.Pro3728Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000974 in 1,612,536 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3728S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2	c.11182C>G	p.Pro3728Ala	missense_variant	75/93	ENST00000327475.11
DNAH8-AS1	NR_038401.1	n.161-4523G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11	c.11182C>G	p.Pro3728Ala	missense_variant	75/93	5	NM_001206927.2	P2
DNAH8-AS1	ENST00000416948.1	n.153-4523G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000660 AC: 10 AN: 151498 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 250880 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135568

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1461038 Hom.: 1 Cov.: 31 AF XY: 0.0000894 AC XY: 65 AN XY: 726786

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000660 AC: 10 AN: 151498 Hom.: 0 Cov.: 31 AF XY: 0.0000541 AC XY: 4 AN XY: 73960

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000491 Hom.: 1

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

The c.11182C>G (p.P3728A) alteration is located in exon 75 (coding exon 74) of the DNAH8 gene. This alteration results from a C to G substitution at nucleotide position 11182, causing the proline (P) at amino acid position 3728 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

This sequence change replaces proline with alanine at codon 3728 of the DNAH8 protein (p.Pro3728Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs138016358, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. 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: "Tolerated"; 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	Benign	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.50
MutPred		0.59		.;.;Loss of stability (P = 0.1038);
MVP		0.82
MPC		0.27
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.65

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: rs138016358; hg19: chr6-38897350;