7-21816533-G-A

Variant names:

• chr7-21816533-G-A
• rs2214326
• NM_001277115.2:c.10399G>A

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.10399G>A​(p.Ala3467Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,611,438 control chromosomes in the GnomAD database, including 114,914 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3467S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (12169 hom., cov: 31)
  • Exomes 𝑓: 0.36 (102745 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.144
• Publications: 26 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, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124901599 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.241899E-6).
• BP6: Variant 7-21816533-G-A is Benign according to our data. Variant chr7-21816533-G-A is described in ClinVar as Benign. ClinVar VariationId is 178732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 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.10399G>A	p.Ala3467Thr	missense	Exon 64 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.10399G>A	p.Ala3467Thr	missense	Exon 64 of 82	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58785 AN: 151738 Hom.: 12156 Cov.: 31

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.389

GnomAD2 exomes AF: 0.420 AC: 103281 AN: 246088 AF XY: 0.412

Gnomad AFR exome AF: 0.390

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.363 AC: 530277 AN: 1459582 Hom.: 102745 Cov.: 46 AF XY: 0.364 AC XY: 264150 AN XY: 725854

African (AFR) AF: 0.395 AC: 13198 AN: 33448

American (AMR) AF: 0.546 AC: 24204 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 7248 AN: 26088

East Asian (EAS) AF: 0.823 AC: 32604 AN: 39628

South Asian (SAS) AF: 0.424 AC: 36362 AN: 85794

European-Finnish (FIN) AF: 0.356 AC: 18987 AN: 53326

Middle Eastern (MID) AF: 0.422 AC: 2433 AN: 5766

European-Non Finnish (NFE) AF: 0.335 AC: 372441 AN: 1110902

Other (OTH) AF: 0.378 AC: 22800 AN: 60308

GnomAD4 genome AF: 0.387 AC: 58840 AN: 151856 Hom.: 12169 Cov.: 31 AF XY: 0.395 AC XY: 29310 AN XY: 74202

African (AFR) AF: 0.393 AC: 16240 AN: 41374

American (AMR) AF: 0.483 AC: 7361 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 926 AN: 3470

East Asian (EAS) AF: 0.818 AC: 4224 AN: 5164

South Asian (SAS) AF: 0.427 AC: 2051 AN: 4808

European-Finnish (FIN) AF: 0.363 AC: 3823 AN: 10530

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22996 AN: 67946

Other (OTH) AF: 0.387 AC: 818 AN: 2112

Alfa AF: 0.361 Hom.: 47389

Bravo AF: 0.399

TwinsUK AF: 0.343 AC: 1270

ALSPAC AF: 0.357 AC: 1375

ESP6500AA AF: 0.385 AC: 1532

ESP6500EA AF: 0.330 AC: 2736

ExAC AF: 0.409 AC: 49439

Asia WGS AF: 0.574 AC: 1997 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	0.065
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.013
DANN	Benign	0.39
DEOGEN2	Benign	0.024	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.14
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.089
Sift	Benign	1.0	T
Vest4		0.018
ClinPred		0.013	T
GERP RS		-12
Varity_R		0.055
gMVP		0.096
Mutation Taster		=100/0	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: rs2214326; hg19: chr7-21856151; COSMIC: COSV104657311;