chr6-38929574-C-T

Variant names:

• chr6-38929574-C-T
• rs138016358
• NM_001206927.2:c.11182C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001206927.2(DNAH8):​c.11182C>T​(p.Pro3728Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,612,630 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3728A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.02
• Publications: 5 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-AS1 (HGNC:40188): (DNAH8 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043050945).
• BP6: Variant 6-38929574-C-T is Benign according to our data. Variant chr6-38929574-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 407297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00142 (215/151610) while in subpopulation AMR AF = 0.00401 (61/15204). AF 95% confidence interval is 0.00321. There are 2 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.11182C>T	p.Pro3728Ser	missense	Exon 75 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.10531C>T	p.Pro3511Ser	missense	Exon 74 of 92	NP_001362.2
	DNAH8-AS1	NR_038401.1		n.161-4523G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.11182C>T	p.Pro3728Ser	missense	Exon 75 of 93	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.10531C>T	p.Pro3511Ser	missense	Exon 73 of 91	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.11182C>T	p.Pro3728Ser	missense	Exon 74 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 215 AN: 151496 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00402

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 250880 AF XY: 0.00105

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00244 AC: 3566 AN: 1461020 Hom.: 8 Cov.: 31 AF XY: 0.00239 AC XY: 1734 AN XY: 726780

African (AFR) AF: 0.000478 AC: 16 AN: 33444

American (AMR) AF: 0.000806 AC: 36 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86178

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53296

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5762

European-Non Finnish (NFE) AF: 0.00306 AC: 3406 AN: 1111510

Other (OTH) AF: 0.00146 AC: 88 AN: 60350

GnomAD4 genome AF: 0.00142 AC: 215 AN: 151610 Hom.: 2 Cov.: 31 AF XY: 0.00126 AC XY: 93 AN XY: 74082

African (AFR) AF: 0.000484 AC: 20 AN: 41356

American (AMR) AF: 0.00401 AC: 61 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10432

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

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 67876

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.00139

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00111 AC: 135

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00241

EpiControl AF: 0.00243

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH8-related disorder Benign:1

May 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH8: BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.41
MVP		0.82
MPC		0.28
ClinPred		0.062	T
GERP RS		5.7
Varity_R		0.57
gMVP		0.75
Mutation Taster		=94/6	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: rs138016358; hg19: chr6-38897350; COSMIC: COSV59427538; COSMIC: COSV59427538;