6-38845575-A-T

Variant names:

• chr6-38845575-A-T
• rs943252271
• NM_001206927.2:c.4847A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001206927.2(DNAH8):​c.4847A>T​(p.Asp1616Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. D1616Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense, splice_region
• Scores: Splicing: ADA: 0.7859
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.22
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

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.4847A>T	p.Asp1616Val	missense splice_region	Exon 36 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.4196A>T	p.Asp1399Val	missense splice_region	Exon 35 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.4847A>T	p.Asp1616Val	missense splice_region	Exon 36 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.4196A>T	p.Asp1399Val	missense splice_region	Exon 34 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.4847A>T	p.Asp1616Val	missense splice_region	Exon 35 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460584 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726692

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110924

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Primary ciliary dyskinesia (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.51		Loss of disorder (P = 0.0739)
MVP		0.82
MPC		0.61
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.82
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Pathogenic	0.77
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: rs943252271; hg19: chr6-38813351; COSMIC: COSV100543756;