rs72655967

chr7-21543303-C-Achr7-21543303-C-T

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.58C>A(p.Arg20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000973 in 1,549,134 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. R20C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (14 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.343

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=0.0040258765).
• BP6: Variant 7-21543303-C-A is Benign according to our data. Variant chr7-21543303-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218583.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00187 (285/152310) while in subpopulation AMR AF= 0.0161 (247/15308). AF 95% confidence interval is 0.0145. There are 4 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.58C>A	p.Arg20Ser	missense_variant	1/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.58C>A	p.Arg20Ser	missense_variant	1/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152192 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00549 AC: 826 AN: 150532 Hom.: 9 AF XY: 0.00408 AC XY: 328 AN XY: 80354

Gnomad AFR exome AF: 0.000278

Gnomad AMR exome AF: 0.0318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00242

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000694

Gnomad OTH exome AF: 0.00304

GnomAD4 exome AF: 0.000876 AC: 1223 AN: 1396824 Hom.: 14 Cov.: 32 AF XY: 0.000757 AC XY: 521 AN XY: 688692

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.0290

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00328

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.000829

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152310 Hom.: 4 Cov.: 33 AF XY: 0.00236 AC XY: 176 AN XY: 74478

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000972

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000698 Hom.: 1

Bravo AF: 0.00331

ExAC AF: 0.000451 AC: 20

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg20Ser in exon 1 of DNAH11: This variant is not expected to have clinical sign ificance because it has been identified in 3.8% (5/132) of Mexican chromosomes f rom a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/ projects/SNP; dbSNP rs72655967). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 16, 2017	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	9.5
Dann	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.42	T;T;T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
Polyphen		0.093	.;.;B
Vest4		0.20
MVP		0.085
ClinPred		0.017	T
GERP RS		-0.63
Varity_R		0.36
gMVP		0.43

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: rs72655967; hg19: chr7-21582921;