rs148698911

Positions:

• chr6-38873139-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001206927.2(DNAH8):​c.7471A>G​(p.Ile2491Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,613,520 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.27

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008616328).
• BP6: Variant 6-38873139-A-G is Benign according to our data. Variant chr6-38873139-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 525564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000959 (146/152292) while in subpopulation AFR AF= 0.00298 (124/41570). AF 95% confidence interval is 0.00256. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.7471A>G	p.Ile2491Val	missense_variant	51/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.7471A>G	p.Ile2491Val	missense_variant	51/93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.6820A>G	p.Ile2274Val	missense_variant	49/91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.7471A>G	p.Ile2491Val	missense_variant	50/82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000328 AC: 82 AN: 250318 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135336

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000204 AC: 298 AN: 1461228 Hom.: 1 Cov.: 34 AF XY: 0.000186 AC XY: 135 AN XY: 726972

Gnomad4 AFR exome AF: 0.00412

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000946

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74472

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.00133

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000436 AC: 53

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Spermatogenic failure 46 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T;T;T
Eigen	Benign	0.058
Eigen_PC	Benign	0.097
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	.;.;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.91	.;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.25	.;T;T
Polyphen		0.74	.;.;P
Vest4		0.51
MVP		0.72
MPC		0.16
ClinPred		0.080	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148698911; hg19: chr6-38840915;