rs61758417

Variant names:

• chr6-38872716-G-T
• rs61758417
• NM_001206927.2:c.7171G>T
• DNAH8 p.Ala2391Ser

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206927.2(DNAH8):​c.7171G>T​(p.Ala2391Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,060 control chromosomes in the GnomAD database, including 909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (91 hom., cov: 33)
  • Exomes 𝑓: 0.011 (818 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.92
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022349358).
• BP6: Variant 6-38872716-G-T is Benign according to our data. Variant chr6-38872716-G-T is described in ClinVar as Benign. ClinVar VariationId is 414424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

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.7171G>T	p.Ala2391Ser	missense	Exon 50 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.6520G>T	p.Ala2174Ser	missense	Exon 49 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.7171G>T	p.Ala2391Ser	missense	Exon 50 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.6520G>T	p.Ala2174Ser	missense	Exon 48 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.7171G>T	p.Ala2391Ser	missense	Exon 49 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1576 AN: 152154 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.0967

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.0250 AC: 6272 AN: 251102 AF XY: 0.0280

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0112 AC: 16393 AN: 1461788 Hom.: 818 Cov.: 32 AF XY: 0.0136 AC XY: 9919 AN XY: 727208

African (AFR) AF: 0.00120 AC: 40 AN: 33470

American (AMR) AF: 0.0143 AC: 639 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00448 AC: 117 AN: 26134

East Asian (EAS) AF: 0.135 AC: 5338 AN: 39670

South Asian (SAS) AF: 0.0888 AC: 7662 AN: 86258

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53418

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.00132 AC: 1473 AN: 1111954

Other (OTH) AF: 0.0167 AC: 1006 AN: 60394

GnomAD4 genome AF: 0.0103 AC: 1568 AN: 152272 Hom.: 91 Cov.: 33 AF XY: 0.0127 AC XY: 948 AN XY: 74448

African (AFR) AF: 0.00204 AC: 85 AN: 41566

American (AMR) AF: 0.00726 AC: 111 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.147 AC: 763 AN: 5176

South Asian (SAS) AF: 0.0960 AC: 463 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68016

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00880 Hom.: 179

Bravo AF: 0.00951

Asia WGS AF: 0.104 AC: 359 AN: 3476

EpiCase AF: 0.00267

EpiControl AF: 0.00285

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.023	D
Varity_R		0.35
gMVP		0.28
Mutation Taster		=96/4	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs61758417;

hg19: chr6-38840492;

COSMIC: COSV100543493;

COSMIC: COSV100543493;