chr7-21861899-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001277115.2(DNAH11):c.11249T>G(p.Val3750Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 0.925

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015707612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2 link	c.11249T>G	p.Val3750Gly	missense_variant	Exon 69 of 82	ENST00000409508.8	NP_001264044.1	Q96DT5Q96NT7H9NAJ8H9NAJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH11	ENST00000409508.8 link	c.11249T>G	p.Val3750Gly	missense_variant	Exon 69 of 82	5	NM_001277115.2	ENSP00000475939.1	Q96DT5
DNAH11	ENST00000421290.1 link	n.432T>G		non_coding_transcript_exon_variant	Exon 4 of 4	4
DNAH11	ENST00000607413.5 link	n.512T>G		non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000201

AC:

AN:

248410

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000220

AC:

321

AN:

1461420

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

151

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

AC:

AN:

33466

Gnomad4 AMR exome

AF:

0.000201

AC:

AN:

44676

Gnomad4 ASJ exome

AF:

0.00226

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39686

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86198

Gnomad4 FIN exome

AF:

0.0000187

AC:

AN:

53384

Gnomad4 NFE exome

AF:

0.000214

AC:

238

AN:

1111748

Gnomad4 Remaining exome

AF:

0.000166

AC:

AN:

60362

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000230

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0000241

AC:

0.0000240709

AN:

0.0000240709

Gnomad4 AMR

AF:

0.000523

AC:

0.000523013

AN:

0.000523013

Gnomad4 ASJ

AF:

0.00288

AC:

0.00288184

AN:

0.00288184

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000235

AC:

0.000235246

AN:

0.000235246

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000296

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000357

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 08, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V3750G variant (also known as c.11249T>G), located in coding exon 69 of the DNAH11 gene, results from a T to G substitution at nucleotide position 11249. The valine at codon 3750 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to betolerated by SIFT in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 7

Uncertain:2

Aug 14, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DNAH11 c.11249T>G (p.Val3750Gly) variant, to our knowledge, has not been reported in the medical literature in an individual with primary ciliary dyskinesia but has been reported in the ClinVar database as a germline variant of uncertain significance by three submitters and a benign variant by one submitter. The overall minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.02% which is lower than the incidence of autosomal recessive primary ciliary dyskinesia. The valine at this codon is not conserved across vertebrates and computational predictors suggest that the variant does not impact DNAH11 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Apr 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DNAH11 c.11249T>G (p.Val3750Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 248410 control chromosomes (gnomAD). To our knowledge, no occurrence of c.11249T>G in individuals affected with Primary Ciliary Dyskinesia 7 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 359677). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.043

.;.;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.48

T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

.;N;.

REVEL

Benign

0.032

Sift

Benign

0.25

.;T;.

Vest4

0.21

MVP

0.41

ClinPred

0.023

GERP RS

0.39

Varity_R

0.060

gMVP

0.37

Mutation Taster

=91/9

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over