rs6966525

chr7-21543433-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001277115.2(DNAH11):c.188G>C(p.Gly63Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000587 in 1,558,042 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.60

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055802763).
• BP6: Variant 7-21543433-G-C is Benign according to our data. Variant chr7-21543433-G-C is described in ClinVar as [Benign]. Clinvar id is 257876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00311 (474/152366) while in subpopulation AFR AF= 0.0108 (450/41602). AF 95% confidence interval is 0.00999. There are 3 homozygotes in gnomad4. There are 222 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.188G>C	p.Gly63Ala	missense_variant	1/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.188G>C	p.Gly63Ala	missense_variant	1/82	5	NM_001277115.2	P1
DNAH11	ENST00000607050.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 468 AN: 152248 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000683 AC: 112 AN: 163904 Hom.: 1 AF XY: 0.000527 AC XY: 46 AN XY: 87324

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000476

Gnomad ASJ exome AF: 0.000116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000307

Gnomad OTH exome AF: 0.000218

GnomAD4 exome AF: 0.000314 AC: 441 AN: 1405676 Hom.: 1 Cov.: 35 AF XY: 0.000284 AC XY: 197 AN XY: 693908

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.000746

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000305

Gnomad4 OTH exome AF: 0.000772

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152366 Hom.: 3 Cov.: 33 AF XY: 0.00298 AC XY: 222 AN XY: 74514

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000915 Hom.: 1

Bravo AF: 0.00333

ESP6500AA AF: 0.00915 AC: 35

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000657 AC: 76

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	20
Dann	Benign	0.90
Eigen	Benign	0.065
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	T;T;T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.59	T
Polyphen		0.95	.;.;P
Vest4		0.22
MVP		0.23
ClinPred		0.024	T
GERP RS		4.0
Varity_R		0.24
gMVP		0.35

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: rs6966525; hg19: chr7-21583051;