rs199629774

Positions:

• chr7-21617725-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):​c.4202A>G​(p.Gln1401Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00154 in 1,613,138 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 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. Q1401H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (17 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.18

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010043949).
• BP6: Variant 7-21617725-A-G is Benign according to our data. Variant chr7-21617725-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257890.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=1, Uncertain_significance=1}. Variant chr7-21617725-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00102 (155/152356) while in subpopulation SAS AF= 0.00828 (40/4828). AF 95% confidence interval is 0.00625. There are 1 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.4202A>G	p.Gln1401Arg	missense_variant	23/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.4202A>G	p.Gln1401Arg	missense_variant	23/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 156 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00236 AC: 584 AN: 247820 Hom.: 7 AF XY: 0.00289 AC XY: 389 AN XY: 134474

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00512

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0117

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00159 AC: 2327 AN: 1460782 Hom.: 17 Cov.: 31 AF XY: 0.00191 AC XY: 1388 AN XY: 726650

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00487

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0112

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000935

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.00119 AC XY: 89 AN XY: 74510

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00142 Hom.: 2

Bravo AF: 0.000903

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00145 AC: 12

ExAC AF: 0.00255 AC: 308

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00137

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 15, 2018	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

DNAH11: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	D;D;T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.4	.;D;.
REVEL	Benign	0.24
Sift	Benign	0.083	.;T;.
Vest4		0.59
MVP		0.51
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.41
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs199629774; hg19: chr7-21657343;