rs762297426

chr7-21854360-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001277115.2(DNAH11):c.11107G>C(p.Glu3703Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,613,628 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3703K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.02

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022090137).
• BP6: Variant 7-21854360-G-C is Benign according to our data. Variant chr7-21854360-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 410853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.11107G>C	p.Glu3703Gln	missense_variant	68/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.11107G>C	p.Glu3703Gln	missense_variant	68/82	5	NM_001277115.2	P1
DNAH11	ENST00000421290.1	n.290G>C		non_coding_transcript_exon_variant	3/4	4
DNAH11	ENST00000607413.5	n.370G>C		non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152074 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000289 AC: 72 AN: 248922 Hom.: 1 AF XY: 0.000259 AC XY: 35 AN XY: 135068

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00547

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000184 AC: 269 AN: 1461554 Hom.: 1 Cov.: 29 AF XY: 0.000177 AC XY: 129 AN XY: 727050

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152074 Hom.: 0 Cov.: 33 AF XY: 0.000189 AC XY: 14 AN XY: 74268

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.000246

ExAC AF: 0.000207 AC: 25

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 09, 2022	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

DNAH11: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-0.50	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
Vest4		0.50
MutPred		0.34		Gain of MoRF binding (P = 0.0471);Gain of MoRF binding (P = 0.0471);.;
MVP		0.85
ClinPred		0.20	T
GERP RS		4.7
Varity_R		0.35
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762297426; hg19: chr7-21893978;