rs140085329

chr7-21558986-G-Cchr7-21558986-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001277115.2(DNAH11):c.680G>C(p.Cys227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,578,022 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.120

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073696077).
• BP6: Variant 7-21558986-G-C is Benign according to our data. Variant chr7-21558986-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 410854.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.680G>C	p.Cys227Ser	missense_variant	3/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.680G>C	p.Cys227Ser	missense_variant	3/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000293 AC: 56 AN: 191076 Hom.: 0 AF XY: 0.000483 AC XY: 49 AN XY: 101358

Gnomad AFR exome AF: 0.0000884

Gnomad AMR exome AF: 0.0000359

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 169 AN: 1425760 Hom.: 2 Cov.: 31 AF XY: 0.000193 AC XY: 136 AN XY: 705442

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.0000510

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000458

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.000226 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 25, 2024	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.39
Dann	Benign	0.33
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
Polyphen		0.0	.;.;B
Vest4		0.16
MutPred		0.44		Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);
MVP		0.040
ClinPred		0.0063	T
GERP RS		-3.5
Varity_R		0.043
gMVP		0.093

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: rs140085329; hg19: chr7-21598604;