rs1678729

Positions:

• chr6-38832433-T-A
• chr6-38832433-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001206927.2(DNAH8):​c.4300T>A​(p.Leu1434Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1434L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH8 NM_001206927.2 missense, splice_region
• Scores: Splicing: ADA: 0.00003249
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0940

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047949553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.4300T>A	p.Leu1434Met	missense_variant, splice_region_variant	31/93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.4300T>A	p.Leu1434Met	missense_variant, splice_region_variant	31/93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.3649T>A	p.Leu1217Met	missense_variant, splice_region_variant	29/91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.4300T>A	p.Leu1434Met	missense_variant, splice_region_variant	30/82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.20
DANN	Benign	0.83
DEOGEN2	Benign	0.0079	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	.;.;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.31	.;N;N
REVEL	Benign	0.0090
Sift	Benign	0.12	.;T;T
Polyphen		0.0010	.;.;B
Vest4		0.099
MutPred		0.36		.;.;Gain of disorder (P = 0.0575);
MVP		0.17
MPC		0.12
ClinPred		0.048	T
GERP RS		-5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0020
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: rs1678729; hg19: chr6-38800209;