rs4832089

Variant names:

• chr2-84528925-G-A
• rs4832089
• NM_001370.2:c.421G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-84528925-G-A
• chr2-84528925-G-C
• chr2-84528925-G-T

Variant summary

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

The NM_001370.2(DNAH6):​c.421G>A​(p.Val141Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.946 in 1,549,342 control chromosomes in the GnomAD database, including 694,396 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65940 hom., cov: 25)
  • Exomes 𝑓: 0.95 (628456 hom.)
• Consequence: DNAH6 NM_001370.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34
• Publications: 21 publications found

Genes affected

DNAH6 (HGNC:2951): (dynein axonemal heavy chain 6) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Mutations in this gene may cause primary ciliary dyskinesia (PCD) as well as heterotaxy. [provided by RefSeq, Jun 2016]

DNAH6 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=9.98577E-7).
• BP6: Variant 2-84528925-G-A is Benign according to our data. Variant chr2-84528925-G-A is described in ClinVar as Benign. ClinVar VariationId is 402731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370.2. 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
	DNAH6	NM_001370.2	MANE Select	c.421G>A	p.Val141Met	missense	Exon 4 of 77	NP_001361.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH6	ENST00000389394.8	TSL:5 MANE Select	c.421G>A	p.Val141Met	missense	Exon 4 of 77	ENSP00000374045.3
	DNAH6	ENST00000494025.1	TSL:1	n.229+10874G>A		intron	N/A
	DNAH6	ENST00000468661.1	TSL:4	n.454+3187G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.933 AC: 140971 AN: 151042 Hom.: 65906 Cov.: 25

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.954

Gnomad ASJ AF: 0.985

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.950

Gnomad FIN AF: 0.960

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.946

GnomAD2 exomes AF: 0.956 AC: 149258 AN: 156142 AF XY: 0.957

Gnomad AFR exome AF: 0.880

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.947

Gnomad OTH exome AF: 0.959

GnomAD4 exome AF: 0.948 AC: 1325338 AN: 1398186 Hom.: 628456 Cov.: 45 AF XY: 0.948 AC XY: 654069 AN XY: 689624

African (AFR) AF: 0.877 AC: 27655 AN: 31522

American (AMR) AF: 0.971 AC: 34644 AN: 35670

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 24799 AN: 25150

East Asian (EAS) AF: 0.999 AC: 35676 AN: 35710

South Asian (SAS) AF: 0.952 AC: 75406 AN: 79178

European-Finnish (FIN) AF: 0.962 AC: 47373 AN: 49254

Middle Eastern (MID) AF: 0.958 AC: 5444 AN: 5682

European-Non Finnish (NFE) AF: 0.946 AC: 1019415 AN: 1078078

Other (OTH) AF: 0.948 AC: 54926 AN: 57942

GnomAD4 genome AF: 0.933 AC: 141059 AN: 151156 Hom.: 65940 Cov.: 25 AF XY: 0.935 AC XY: 68943 AN XY: 73772

African (AFR) AF: 0.882 AC: 36268 AN: 41126

American (AMR) AF: 0.954 AC: 14475 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.985 AC: 3413 AN: 3466

East Asian (EAS) AF: 0.997 AC: 5124 AN: 5138

South Asian (SAS) AF: 0.950 AC: 4471 AN: 4708

European-Finnish (FIN) AF: 0.960 AC: 9964 AN: 10384

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64244 AN: 67856

Other (OTH) AF: 0.946 AC: 1985 AN: 2098

Alfa AF: 0.945 Hom.: 197628

Bravo AF: 0.932

TwinsUK AF: 0.943 AC: 3497

ALSPAC AF: 0.947 AC: 3651

ESP6500AA AF: 0.872 AC: 1207

ESP6500EA AF: 0.946 AC: 3010

ExAC AF: 0.944 AC: 22356

Asia WGS AF: 0.967 AC: 3362 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.034
DANN	Benign	0.68
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-1.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.0040
Sift	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.026
MPC		0.082
ClinPred		0.0030	T
GERP RS		-5.8
Varity_R		0.027
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: rs4832089; hg19: chr2-84756049; COSMIC: COSV107253625;