rs61757219

Variant names:

• chr6-38845636-G-T
• rs61757219
• NM_001206927.2:c.4908G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001206927.2(DNAH8):​c.4908G>T​(p.Glu1636Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,613,928 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (71 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.27

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004161775).
• BP6: Variant 6-38845636-G-T is Benign according to our data. Variant chr6-38845636-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 238649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00497 (757/152254) while in subpopulation SAS AF= 0.0191 (92/4816). AF 95% confidence interval is 0.0159. There are 4 homozygotes in gnomad4. There are 366 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.4908G>T	p.Glu1636Asp	missense_variant	Exon 36 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.4908G>T	p.Glu1636Asp	missense_variant	Exon 36 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.4257G>T	p.Glu1419Asp	missense_variant	Exon 34 of 91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.4908G>T	p.Glu1636Asp	missense_variant	Exon 35 of 82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152136 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00706 AC: 1770 AN: 250884 Hom.: 19 AF XY: 0.00825 AC XY: 1118 AN XY: 135560

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0223

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00743

Gnomad OTH exome AF: 0.00654

GnomAD4 exome AF: 0.00680 AC: 9939 AN: 1461674 Hom.: 71 Cov.: 31 AF XY: 0.00737 AC XY: 5357 AN XY: 727154

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0226

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00640

Gnomad4 OTH exome AF: 0.00671

GnomAD4 genome AF: 0.00497 AC: 757 AN: 152254 Hom.: 4 Cov.: 32 AF XY: 0.00492 AC XY: 366 AN XY: 74448

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00735

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00685 Hom.: 5

Bravo AF: 0.00486

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00748 AC: 908

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00976

EpiControl AF: 0.00854

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spermatogenic failure 46 Benign:1

Dec 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0098	T;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	.;.;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.51	.;N;N
REVEL	Benign	0.062
Sift	Benign	0.44	.;T;T
Polyphen		0.30	.;.;B
Vest4		0.18
MutPred		0.44		.;.;Loss of helix (P = 0.2271);
MVP		0.54
MPC		0.11
ClinPred		0.0067	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61757219; hg19: chr6-38813412;