7-21892549-C-T

Position:

• chr7-21892549-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.12632C>T​(p.Pro4211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,956 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 3.42

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=0.017279118).
• BP6: Variant 7-21892549-C-T is Benign according to our data. Variant chr7-21892549-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220048.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00124 (1810/1461694) while in subpopulation MID AF= 0.0052 (30/5766). AF 95% confidence interval is 0.00374. There are 4 homozygotes in gnomad4_exome. There are 1006 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.12632C>T	p.Pro4211Leu	missense_variant	77/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.12632C>T	p.Pro4211Leu	missense_variant	77/82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00144 AC: 360 AN: 249260 Hom.: 0 AF XY: 0.00160 AC XY: 217 AN XY: 135232

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00418

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00124 AC: 1810 AN: 1461694 Hom.: 4 Cov.: 33 AF XY: 0.00138 AC XY: 1006 AN XY: 727130

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00399

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74456

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000921 Hom.: 0

Bravo AF: 0.000922

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.00121 AC: 10

ExAC AF: 0.00148 AC: 179

EpiCase AF: 0.00158

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DNAH11: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Primary ciliary dyskinesia 7 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 08, 2019	This DNAH11 variant (rs142585703) has been identified in large population datasets and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within a subpopulation (gnomAD global frequency: 379/280652 alleles; 0.1350%, no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as benign, one as likely benign and two as a variant of uncertain clinical significance. Two bioinformatic tools queried predict that this substitution would be probably damaging, and the proline residue at this position is evolutionarily conserved across most species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 77 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence that this variant is deleterious, the clinical significance of c.12632C>T is uncertain at this time. -

Primary ciliary dyskinesia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-9.1	.;D;.
REVEL	Benign	0.16
Sift	Benign	0.032	.;D;.
Vest4		0.27
MVP		0.32
ClinPred		0.090	T
GERP RS		5.1
Varity_R		0.64
gMVP		0.37

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: rs142585703; hg19: chr7-21932167;