7-21742035-A-G

Variant names:

• chr7-21742035-A-G
• rs72657364
• NM_001277115.2:c.8023A>G

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.8023A>G​(p.Ile2675Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,914 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2675F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (8 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.670
• Publications: 11 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• 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=0.0054730177).
• BP6: Variant 7-21742035-A-G is Benign according to our data. Variant chr7-21742035-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257933.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00315 (480/152266) while in subpopulation AFR AF = 0.00815 (339/41572). AF 95% confidence interval is 0.00744. There are 1 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,AD 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.8023A>G	p.Ile2675Val	missense	Exon 49 of 82	NP_001264044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.8023A>G	p.Ile2675Val	missense	Exon 49 of 82	ENSP00000475939.1
	DNAH11	ENST00000605912.1	TSL:3	c.474+2362A>G		intron	N/A	ENSP00000476068.1

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 477 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00176 AC: 438 AN: 249166 AF XY: 0.00164

Gnomad AFR exome AF: 0.00756

Gnomad AMR exome AF: 0.00345

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00228

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00145 AC: 2120 AN: 1461648 Hom.: 8 Cov.: 31 AF XY: 0.00144 AC XY: 1044 AN XY: 727112

African (AFR) AF: 0.00759 AC: 254 AN: 33470

American (AMR) AF: 0.00371 AC: 166 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0102 AC: 406 AN: 39698

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53398

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000991 AC: 1102 AN: 1111840

Other (OTH) AF: 0.00200 AC: 121 AN: 60374

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74452

African (AFR) AF: 0.00815 AC: 339 AN: 41572

American (AMR) AF: 0.00281 AC: 43 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68006

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00176 Hom.: 2

Bravo AF: 0.00375

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00737 AC: 28

ESP6500EA AF: 0.000846 AC: 7

ExAC AF: 0.00204 AC: 246

EpiCase AF: 0.00120

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.16
DANN	Benign	0.17
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.67
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.014
Sift	Benign	1.0	T
Vest4		0.10
MVP		0.12
ClinPred		0.000013	T
GERP RS		-1.3
Varity_R		0.021
gMVP		0.22
Mutation Taster		=100/0	polymorphism

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: rs72657364; hg19: chr7-21781653;