NM_001206927.2:c.5140C>A

Variant names:

• chr6-38848742-C-A
• rs1060501470
• NM_001206927.2:c.5140C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001206927.2(DNAH8):​c.5140C>A​(p.Leu1714Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L1714V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.5140C>A	p.Leu1714Ile	missense	Exon 37 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.4489C>A	p.Leu1497Ile	missense	Exon 36 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.5140C>A	p.Leu1714Ile	missense	Exon 37 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.4489C>A	p.Leu1497Ile	missense	Exon 35 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.5140C>A	p.Leu1714Ile	missense	Exon 36 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.0075	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		3.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.57		Gain of helix (P = 0.2294)
MVP		0.76
MPC		0.60
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.34
gMVP		0.22
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs1060501470; hg19: chr6-38816518; COSMIC: COSV59422153;