7-21615131-G-C

Variant names:

• chr7-21615131-G-C
• rs200954442
• NM_001277115.2:c.3870G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001277115.2(DNAH11):​c.3870G>C​(p.Glu1290Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,611,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1290E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.704
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059773624).
• BP6: Variant 7-21615131-G-C is Benign according to our data. Variant chr7-21615131-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416418.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00171 (260/152294) while in subpopulation AFR AF = 0.00596 (248/41576). AF 95% confidence interval is 0.00536. There are 0 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277115.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.3870G>C	p.Glu1290Asp	missense	Exon 21 of 82	NP_001264044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.3870G>C	p.Glu1290Asp	missense	Exon 21 of 82	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000446 AC: 110 AN: 246636 AF XY: 0.000276

Gnomad AFR exome AF: 0.00630

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000145 AC: 211 AN: 1459482 Hom.: 0 Cov.: 30 AF XY: 0.000117 AC XY: 85 AN XY: 725964

African (AFR) AF: 0.00449 AC: 150 AN: 33380

American (AMR) AF: 0.000316 AC: 14 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 85692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1110966

Other (OTH) AF: 0.000299 AC: 18 AN: 60300

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74456

African (AFR) AF: 0.00596 AC: 248 AN: 41576

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.00175

ESP6500AA AF: 0.00565 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000563 AC: 68

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000549

EpiControl AF: 0.0000596

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Oct 14, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Jan 24, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.70
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.041
Sift	Benign	0.25	T
Polyphen		0.65	P
Vest4		0.20
MutPred		0.32		Gain of helix (P = 0.0496)
MVP		0.34
ClinPred		0.013	T
GERP RS		4.2
Varity_R		0.057
gMVP		0.27
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200954442; hg19: chr7-21654749;