6-38875744-C-T

Variant names:

• chr6-38875744-C-T
• rs113332942
• NM_001206927.2:c.7774C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001206927.2(DNAH8):​c.7774C>T​(p.Arg2592Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,852 control chromosomes in the GnomAD database, including 3 homozygotes. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.793
• Publications: 4 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000637 (97/152166) while in subpopulation NFE AF = 0.00112 (76/68008). AF 95% confidence interval is 0.000915. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.7774C>T	p.Arg2592Trp	missense	Exon 53 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.7123C>T	p.Arg2375Trp	missense	Exon 52 of 92	NP_001362.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.7774C>T	p.Arg2592Trp	missense	Exon 53 of 93	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.7123C>T	p.Arg2375Trp	missense	Exon 51 of 91	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.7774C>T	p.Arg2592Trp	missense	Exon 52 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000502 AC: 126 AN: 251198 AF XY: 0.000457

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00125 AC: 1833 AN: 1461686 Hom.: 2 Cov.: 32 AF XY: 0.00118 AC XY: 856 AN XY: 727144

African (AFR) AF: 0.000269 AC: 9 AN: 33470

American (AMR) AF: 0.000224 AC: 10 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39658

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53390

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00158 AC: 1756 AN: 1111902

Other (OTH) AF: 0.000729 AC: 44 AN: 60388

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74406

African (AFR) AF: 0.000313 AC: 13 AN: 41526

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68008

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000876 Hom.: 0

Bravo AF: 0.000650

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia (2)
-	2	-	Spermatogenic failure 46 (2)
-	1	-	DNAH8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.79
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.26
Sift	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.81
MVP		0.69
MPC		0.13
ClinPred		0.11	T
GERP RS		0.21
Varity_R		0.28
gMVP		0.71
Mutation Taster		=81/19	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: rs113332942; hg19: chr6-38843520;