7-21543247-T-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate 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 (★★). Synonymous variant affecting the same amino acid position (i.e. MAAQVAAREARDFREAPTLRLTSGAGLEAVGAVELEEEEENEEEAAARRARSFAQDARVRFLGGRLAMMLGFTEEKWSQYLESEDNRQVLGEFLESTSPACLVFSFAASGRLAASQ1GAP?) has been classified as 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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001277115.2 (DNAH11) was described as [Likely_pathogenic] in ClinVar as 454666
• 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/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.2T>G	p.Met1?	start_lost	1/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.2T>G	p.Met1?	start_lost	1/82	5	NM_001277115.2	P1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2017

- -

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
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
MutationTaster	Benign	1.0	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;