rs6461613

Variant names:

• chr7-21884396-A-G
• rs6461613
• NM_001277115.2:c.12493A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-21884396-A-G
• chr7-21884396-A-T

Variant summary

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

The NM_001277115.2(DNAH11):​c.12493A>G​(p.Met4165Val) variant causes a missense change. The variant allele was found at a frequency of 0.802 in 1,608,656 control chromosomes in the GnomAD database, including 528,502 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (39739 hom., cov: 32)
  • Exomes 𝑓: 0.81 (488763 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.69
• Publications: 28 publications found

Genes affected

DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]

DNAH11 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=8.890553E-7).
• BP6: Variant 7-21884396-A-G is Benign according to our data. Variant chr7-21884396-A-G is described in ClinVar as Benign. ClinVar VariationId is 178735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277115.2. 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
	DNAH11	NM_001277115.2	MANE Select	c.12493A>G	p.Met4165Val	missense	Exon 76 of 82	NP_001264044.1	Q96DT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.12493A>G	p.Met4165Val	missense	Exon 76 of 82	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105726 AN: 152060 Hom.: 39737 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.903

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.819

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.743

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.728

GnomAD2 exomes AF: 0.756 AC: 185702 AN: 245538 AF XY: 0.769

Gnomad AFR exome AF: 0.392

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.828

Gnomad EAS exome AF: 0.685

Gnomad FIN exome AF: 0.862

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.787

GnomAD4 exome AF: 0.814 AC: 1185018 AN: 1456478 Hom.: 488763 Cov.: 40 AF XY: 0.813 AC XY: 589095 AN XY: 724356

African (AFR) AF: 0.379 AC: 12629 AN: 33310

American (AMR) AF: 0.608 AC: 26821 AN: 44082

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 21540 AN: 26022

East Asian (EAS) AF: 0.608 AC: 24045 AN: 39526

South Asian (SAS) AF: 0.749 AC: 63617 AN: 84992

European-Finnish (FIN) AF: 0.863 AC: 46020 AN: 53324

Middle Eastern (MID) AF: 0.780 AC: 4476 AN: 5740

European-Non Finnish (NFE) AF: 0.846 AC: 938105 AN: 1109274

Other (OTH) AF: 0.793 AC: 47765 AN: 60208

GnomAD4 genome AF: 0.695 AC: 105751 AN: 152178 Hom.: 39739 Cov.: 32 AF XY: 0.696 AC XY: 51762 AN XY: 74394

African (AFR) AF: 0.399 AC: 16570 AN: 41498

American (AMR) AF: 0.689 AC: 10538 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.819 AC: 2839 AN: 3468

East Asian (EAS) AF: 0.662 AC: 3422 AN: 5166

South Asian (SAS) AF: 0.743 AC: 3583 AN: 4822

European-Finnish (FIN) AF: 0.874 AC: 9256 AN: 10596

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.837 AC: 56959 AN: 68018

Other (OTH) AF: 0.728 AC: 1536 AN: 2110

Alfa AF: 0.779 Hom.: 22253

Bravo AF: 0.666

TwinsUK AF: 0.854 AC: 3168

ALSPAC AF: 0.848 AC: 3270

ESP6500AA AF: 0.440 AC: 1752

ESP6500EA AF: 0.848 AC: 7150

ExAC AF: 0.755 AC: 91244

Asia WGS AF: 0.673 AC: 2342 AN: 3478

EpiCase AF: 0.841

EpiControl AF: 0.839

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.7
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Vest4		0.11
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.65
gMVP		0.37
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: rs6461613; hg19: chr7-21924014; COSMIC: COSV60943924;