rs928335497

Positions:

• chr7-21818279-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001277115.2(DNAH11):​c.10631A>G​(p.Glu3544Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 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 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.05

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08258006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.10631A>G	p.Glu3544Gly	missense_variant	65/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.10631A>G	p.Glu3544Gly	missense_variant	65/82	5	NM_001277115.2	ENSP00000475939	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247950 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460102 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726310

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.000200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 03, 2023	The c.10631A>G (p.E3544G) alteration is located in exon 65 (coding exon 65) of the DNAH11 gene. This alteration results from a A to G substitution at nucleotide position 10631, causing the glutamic acid (E) at amino acid position 3544 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -

Primary ciliary dyskinesia 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 26, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.060	.;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	.;N;.
REVEL	Benign	0.10
Sift	Benign	0.69	.;T;.
Vest4		0.33
MutPred		0.42		Loss of stability (P = 0.0519);Loss of stability (P = 0.0519);.;
MVP		0.067
ClinPred		0.40	T
GERP RS		5.5
Varity_R		0.077
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: rs928335497; hg19: chr7-21857897;