chr6-38778400-G-A

Variant names:

• chr6-38778400-G-A
• rs61748601
• NM_001206927.2:c.1975G>A

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.1975G>A​(p.Ala659Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,550,288 control chromosomes in the GnomAD database, including 16,848 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1395 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15453 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.719
• Publications: 9 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=0.0015652776).
• BP6: Variant 6-38778400-G-A is Benign according to our data. Variant chr6-38778400-G-A is described in ClinVar as [Benign]. Clinvar id is 402761.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2	c.1975G>A	p.Ala659Thr	missense_variant	Exon 14 of 93	ENST00000327475.11	NP_001193856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11	c.1975G>A	p.Ala659Thr	missense_variant	Exon 14 of 93	5	NM_001206927.2	ENSP00000333363.7
DNAH8	ENST00000359357.7	c.1324G>A	p.Ala442Thr	missense_variant	Exon 12 of 91	2		ENSP00000352312.3
DNAH8	ENST00000449981.6	c.1975G>A	p.Ala659Thr	missense_variant	Exon 13 of 82	5		ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18608 AN: 152002 Hom.: 1385 Cov.: 32

Gnomad AFR AF: 0.0624

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0515

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.134 AC: 32702 AN: 243978 AF XY: 0.128

Gnomad AFR exome AF: 0.0607

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.140 AC: 195835 AN: 1398168 Hom.: 15453 Cov.: 24 AF XY: 0.137 AC XY: 95682 AN XY: 698356

African (AFR) AF: 0.0590 AC: 1894 AN: 32108

American (AMR) AF: 0.264 AC: 11297 AN: 42752

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2826 AN: 25502

East Asian (EAS) AF: 0.0153 AC: 596 AN: 39076

South Asian (SAS) AF: 0.0522 AC: 4304 AN: 82442

European-Finnish (FIN) AF: 0.125 AC: 6599 AN: 52946

Middle Eastern (MID) AF: 0.0942 AC: 515 AN: 5468

European-Non Finnish (NFE) AF: 0.151 AC: 160180 AN: 1059748

Other (OTH) AF: 0.131 AC: 7624 AN: 58126

GnomAD4 genome AF: 0.123 AC: 18652 AN: 152120 Hom.: 1395 Cov.: 32 AF XY: 0.121 AC XY: 8986 AN XY: 74338

African (AFR) AF: 0.0629 AC: 2609 AN: 41506

American (AMR) AF: 0.216 AC: 3296 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3470

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5186

South Asian (SAS) AF: 0.0507 AC: 244 AN: 4816

European-Finnish (FIN) AF: 0.119 AC: 1260 AN: 10564

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

European-Non Finnish (NFE) AF: 0.153 AC: 10420 AN: 67974

Other (OTH) AF: 0.118 AC: 249 AN: 2108

Alfa AF: 0.136 Hom.: 3826

Bravo AF: 0.128

TwinsUK AF: 0.149 AC: 553

ALSPAC AF: 0.161 AC: 620

ESP6500AA AF: 0.0651 AC: 287

ESP6500EA AF: 0.152 AC: 1305

ExAC AF: 0.128 AC: 15532

Asia WGS AF: 0.0790 AC: 277 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.62
DEOGEN2	Benign	0.0077	T;T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.18	.;.;N
PhyloP100		0.72
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.48	.;N;N
REVEL	Benign	0.093
Sift	Benign	0.71	.;T;T
Polyphen		0.0	.;.;B
Vest4		0.094
MPC		0.12
ClinPred		0.0011	T
GERP RS		3.5
Varity_R		0.051
gMVP		0.14
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs61748601; hg19: chr6-38746176; COSMIC: COSV107384592;