rs1016978531

Variant names:

• chr7-21601617-A-C
• rs1016978531
• NM_001277115.2:c.3647A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-21601617-A-C
• chr7-21601617-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001277115.2(DNAH11):​c.3647A>C​(p.Glu1216Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1216K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAH11 NM_001277115.2 missense, splice_region
• Scores: Splicing: ADA: 0.9740
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4225917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.3647A>C	p.Glu1216Ala	missense_variant, splice_region_variant	Exon 18 of 82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.3647A>C	p.Glu1216Ala	missense_variant, splice_region_variant	Exon 18 of 82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1411710 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695286

African (AFR) AF: 0.00 AC: 0 AN: 31860

American (AMR) AF: 0.00 AC: 0 AN: 37660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24514

East Asian (EAS) AF: 0.00 AC: 0 AN: 38768

South Asian (SAS) AF: 0.00 AC: 0 AN: 79532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083378

Other (OTH) AF: 0.00 AC: 0 AN: 58184

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1216 of the DNAH11 protein (p.Glu1216Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNAH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 410867). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;.;M
PhyloP100		7.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.2	.;D;.
REVEL	Benign	0.15
Sift	Benign	0.074	.;T;.
Polyphen		0.75	.;.;P
Vest4		0.38
MutPred		0.41		Loss of disorder (P = 0.0693);Loss of disorder (P = 0.0693);Loss of disorder (P = 0.0693);
MVP		0.56
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.41
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.030		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: rs1016978531; hg19: chr7-21641235;