NM_001206927.2:c.772T>C

Variant names:

• chr6-38737076-T-C
• NM_001206927.2:c.772T>C
• DNAH8 p.Phe258Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001206927.2(DNAH8):​c.772T>C​(p.Phe258Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.36
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

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.772T>C	p.Phe258Leu	missense	Exon 6 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.121T>C	p.Phe41Leu	missense	Exon 5 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.772T>C	p.Phe258Leu	missense	Exon 6 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.121T>C	p.Phe41Leu	missense	Exon 4 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.772T>C	p.Phe258Leu	missense	Exon 5 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1372954 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 680122

African (AFR) AF: 0.00 AC: 0 AN: 28750

American (AMR) AF: 0.00 AC: 0 AN: 25738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23490

East Asian (EAS) AF: 0.00 AC: 0 AN: 35286

South Asian (SAS) AF: 0.00 AC: 0 AN: 68546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076896

Other (OTH) AF: 0.00 AC: 0 AN: 56602

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.0044	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Benign	0.0099
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.19
Sift	Benign	0.13	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.57
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-38704852;