rs145239537

Variant names:

• chr7-21738820-G-A
• rs145239537
• NM_001277115.2:c.7765G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):​c.7765G>A​(p.Val2589Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,605,864 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.37
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006401092).
• BP6: Variant 7-21738820-G-A is Benign according to our data. Variant chr7-21738820-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257931.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00197 (300/152102) while in subpopulation AFR AF = 0.00682 (283/41466). AF 95% confidence interval is 0.00617. There are 2 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.7765G>A	p.Val2589Ile	missense	Exon 47 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.7765G>A	p.Val2589Ile	missense	Exon 47 of 82	ENSP00000475939.1	Q96DT5
	DNAH11	ENST00000605912.1	TSL:3	c.325G>A	p.Val109Ile	missense	Exon 2 of 4	ENSP00000476068.1	U3KQN2

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 151984 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000557 AC: 132 AN: 237088 AF XY: 0.000453

Gnomad AFR exome AF: 0.00758

Gnomad AMR exome AF: 0.000359

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000468

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000261 AC: 380 AN: 1453762 Hom.: 1 Cov.: 30 AF XY: 0.000230 AC XY: 166 AN XY: 722180

African (AFR) AF: 0.00861 AC: 287 AN: 33330

American (AMR) AF: 0.000477 AC: 21 AN: 44034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.000228 AC: 9 AN: 39526

South Asian (SAS) AF: 0.0000832 AC: 7 AN: 84088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52916

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.0000226 AC: 25 AN: 1108030

Other (OTH) AF: 0.000466 AC: 28 AN: 60140

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152102 Hom.: 2 Cov.: 32 AF XY: 0.00186 AC XY: 138 AN XY: 74368

African (AFR) AF: 0.00682 AC: 283 AN: 41466

American (AMR) AF: 0.000524 AC: 8 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000757 Hom.: 2

Bravo AF: 0.00269

ESP6500AA AF: 0.00689 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000619 AC: 75

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.066
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.044	D
Vest4		0.12
MVP		0.31
ClinPred		0.021	T
GERP RS		3.6
Varity_R		0.096
gMVP		0.20
Mutation Taster		=89/11	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: rs145239537; hg19: chr7-21778438; COSMIC: COSV100180937;