rs141818413

Variant names:

• chr6-38803257-A-T
• rs141818413
• NM_001206927.2:c.2980A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-38803257-A-T
• chr6-38803257-A-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001206927.2(DNAH8):​c.2980A>T​(p.Ile994Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 1,609,684 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (1 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 1.46
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• spermatogenic failure 46

  Inheritance: AR Classification: STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• spermatogenic failure 5

  Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027144104).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.2980A>T	p.Ile994Leu	missense	Exon 22 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.2329A>T	p.Ile777Leu	missense	Exon 21 of 92	NP_001362.2	Q96JB1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.2980A>T	p.Ile994Leu	missense	Exon 22 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.2329A>T	p.Ile777Leu	missense	Exon 20 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.2980A>T	p.Ile994Leu	missense	Exon 21 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000676

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000523 AC: 13 AN: 248772 AF XY: 0.0000521

Gnomad AFR exome AF: 0.000680

Gnomad AMR exome AF: 0.0000596

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000316 AC: 46 AN: 1457376 Hom.: 1 Cov.: 28 AF XY: 0.0000276 AC XY: 20 AN XY: 725030

African (AFR) AF: 0.000749 AC: 25 AN: 33368

American (AMR) AF: 0.0000451 AC: 2 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109122

Other (OTH) AF: 0.000183 AC: 11 AN: 60272

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74478

African (AFR) AF: 0.000674 AC: 28 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Primary ciliary dyskinesia (1)
-	1	-	Spermatogenic failure 46 (1)
-	-	-	Primary ciliary dyskinesia;C5436799:Spermatogenic failure 46 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.78
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N
PhyloP100		1.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.36		Gain of catalytic residue at I777 (P = 0.2176)
MVP		0.43
MPC		0.12
ClinPred		0.040	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.42
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs141818413; hg19: chr6-38771033;