NM_001277115.2:c.9098T>C

Variant names:

• chr7-21765585-T-C
• rs28751578
• NM_001277115.2:c.9098T>C

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.9098T>C​(p.Ile3033Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00311 in 1,576,640 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict 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. I3033V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (80 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.84
• Publications: 4 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003173232).
• BP6: Variant 7-21765585-T-C is Benign according to our data. Variant chr7-21765585-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 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.9098T>C	p.Ile3033Thr	missense	Exon 55 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.9098T>C	p.Ile3033Thr	missense	Exon 55 of 82	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2389 AN: 147518 Hom.: 71 Cov.: 31

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00461

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000659

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00388 AC: 928 AN: 239040 AF XY: 0.00318

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000574

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000837

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.00175 AC: 2500 AN: 1428996 Hom.: 80 Cov.: 31 AF XY: 0.00149 AC XY: 1059 AN XY: 710008

African (AFR) AF: 0.0643 AC: 2114 AN: 32898

American (AMR) AF: 0.00238 AC: 103 AN: 43356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24756

East Asian (EAS) AF: 0.00 AC: 0 AN: 39014

South Asian (SAS) AF: 0.000176 AC: 15 AN: 85254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50054

Middle Eastern (MID) AF: 0.00257 AC: 14 AN: 5456

European-Non Finnish (NFE) AF: 0.0000202 AC: 22 AN: 1089846

Other (OTH) AF: 0.00398 AC: 232 AN: 58362

GnomAD4 genome AF: 0.0163 AC: 2400 AN: 147644 Hom.: 71 Cov.: 31 AF XY: 0.0161 AC XY: 1154 AN XY: 71676

African (AFR) AF: 0.0568 AC: 2292 AN: 40352

American (AMR) AF: 0.00461 AC: 67 AN: 14546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.000659 AC: 3 AN: 4554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9454

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.000149 AC: 10 AN: 67016

Other (OTH) AF: 0.0132 AC: 27 AN: 2044

Alfa AF: 0.00798 Hom.: 17

Bravo AF: 0.0182

ESP6500AA AF: 0.0521 AC: 217

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00512 AC: 619

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Primary ciliary dyskinesia (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.8
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.087
Sift	Uncertain	0.021	D
Vest4		0.34
MVP		0.42
ClinPred		0.027	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.21
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28751578; hg19: chr7-21805203;