rs142438011

Positions:

• chr6-39026654-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001206927.2(DNAH8):​c.13823C>T​(p.Thr4608Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,613,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.233

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0058651567).
• BP6: Variant 6-39026654-C-T is Benign according to our data. Variant chr6-39026654-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414429.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0016 (243/152246) while in subpopulation AFR AF= 0.00558 (232/41552). AF 95% confidence interval is 0.00499. There are 1 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.13823C>T	p.Thr4608Met	missense_variant	92/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.13823C>T	p.Thr4608Met	missense_variant	92/93	5	NM_001206927.2	ENSP00000333363	P2
DNAH8	ENST00000359357.7	c.13172C>T	p.Thr4391Met	missense_variant	90/91	2		ENSP00000352312	A2

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.00

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000431 AC: 108 AN: 250390 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135274

Gnomad AFR exome AF: 0.00567

Gnomad AMR exome AF: 0.000260

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: 0.0000176

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000136 AC: 198 AN: 1461074 Hom.: 0 Cov.: 31 AF XY: 0.000113 AC XY: 82 AN XY: 726762

Gnomad4 AFR exome AF: 0.00412

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152246 Hom.: 1 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74436

Gnomad4 AFR AF: 0.00558

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.00185

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000494 AC: 60

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spermatogenic failure 46 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 05, 2021	- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	.;M
MutationTaster	Benign	0.90	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	.;D
REVEL	Benign	0.11
Sift	Benign	0.064	.;T
Polyphen		0.65	.;P
Vest4		0.26
MVP		0.71
MPC		0.40
ClinPred		0.046	T
GERP RS		1.9
Varity_R		0.070
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142438011; hg19: chr6-38994430;