rs1355068287

Variant names:

• chr7-21543247-T-G
• rs1355068287
• NM_001277115.2:c.2T>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Supporting PM2 PP5_Very_Strong

The NM_001277115.2(DNAH11):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,380,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.76

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 201 CDS bases. Genomic position: 21543446. Lost 0.015 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-21543247-T-G is Pathogenic according to our data. Variant chr7-21543247-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 444714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.2T>G	p.Met1?	start_lost	Exon 1 of 82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.2T>G	p.Met1?	start_lost	Exon 1 of 82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000716 AC: 1 AN: 139644 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 75222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 20 AN: 1380956 Hom.: 0 Cov.: 30 AF XY: 0.0000132 AC XY: 9 AN XY: 679404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000187

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Oct 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the DNAH11 mRNA. The next in-frame methionine is located at codon 68. This variant is present in population databases (no rsID available, gnomAD 0.002%). Disruption of the initiator codon has been observed in individual(s) with primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 444714). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	.;.;T
Eigen	Benign	0.0088
Eigen_PC	Benign	0.037
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.79	.;N;.
REVEL	Benign	0.13
Sift	Pathogenic	0.0	.;D;.
Polyphen		0.60	.;.;P
Vest4		0.61
MutPred		0.64		Gain of methylation at M1 (P = 0.0059);Gain of methylation at M1 (P = 0.0059);Gain of methylation at M1 (P = 0.0059);
MVP		0.28
ClinPred		0.66	D
GERP RS		3.5
Varity_R		0.67
gMVP		0.37

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: rs1355068287; hg19: chr7-21582865;