rs61748600

Variant names:

• chr6-38761735-T-C
• rs61748600
• NM_001206927.2:c.1549T>C
• DNAH8 p.Tyr517His

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.1549T>C​(p.Tyr517His) variant causes a missense change. The variant allele was found at a frequency of 0.141 in 1,558,360 control chromosomes in the GnomAD database, including 17,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1386 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16063 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.34
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002126515).
• BP6: Variant 6-38761735-T-C is Benign according to our data. Variant chr6-38761735-T-C is described in ClinVar as Benign. ClinVar VariationId is 402760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.209 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.1549T>C	p.Tyr517His	missense	Exon 11 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.898T>C	p.Tyr300His	missense	Exon 10 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.1549T>C	p.Tyr517His	missense	Exon 11 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.898T>C	p.Tyr300His	missense	Exon 9 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.1549T>C	p.Tyr517His	missense	Exon 10 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18497 AN: 152122 Hom.: 1376 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0510

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.130 AC: 27051 AN: 207336 AF XY: 0.125

Gnomad AFR exome AF: 0.0568

Gnomad AMR exome AF: 0.268

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.144 AC: 201814 AN: 1406120 Hom.: 16063 Cov.: 27 AF XY: 0.140 AC XY: 98181 AN XY: 699940

African (AFR) AF: 0.0564 AC: 1676 AN: 29716

American (AMR) AF: 0.258 AC: 8799 AN: 34078

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2736 AN: 24506

East Asian (EAS) AF: 0.0157 AC: 560 AN: 35766

South Asian (SAS) AF: 0.0530 AC: 4186 AN: 78948

European-Finnish (FIN) AF: 0.123 AC: 6447 AN: 52474

Middle Eastern (MID) AF: 0.0925 AC: 513 AN: 5544

European-Non Finnish (NFE) AF: 0.156 AC: 169225 AN: 1087284

Other (OTH) AF: 0.133 AC: 7672 AN: 57804

GnomAD4 genome AF: 0.122 AC: 18529 AN: 152240 Hom.: 1386 Cov.: 32 AF XY: 0.120 AC XY: 8929 AN XY: 74430

African (AFR) AF: 0.0598 AC: 2487 AN: 41556

American (AMR) AF: 0.215 AC: 3288 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3472

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5190

South Asian (SAS) AF: 0.0506 AC: 244 AN: 4818

European-Finnish (FIN) AF: 0.118 AC: 1252 AN: 10592

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10435 AN: 68008

Other (OTH) AF: 0.118 AC: 249 AN: 2112

Alfa AF: 0.142 Hom.: 5560

Bravo AF: 0.127

Asia WGS AF: 0.0770 AC: 270 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.23
Sift	Benign	0.10	T
Varity_R		0.49
gMVP		0.68
Mutation Taster		=93/7	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: rs61748600;

hg19: chr6-38729511;

COSMIC: COSV59480744;

COSMIC: COSV59480744;