rs1212535211

chr7-21901190-TGAAGAGC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001277115.2(DNAH11):c.13494_13500del(p.Ser4498ArgfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,586 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: 0.0000041 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.94

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]

CDCA7L (HGNC:30777): (cell division cycle associated 7 like) Acts upstream of or within positive regulation of cell population proliferation. Located in cytosol; fibrillar center; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 4586 codons.
• PP5: Variant 7-21901190-TGAAGAGC-T is Pathogenic according to our data. Variant chr7-21901190-TGAAGAGC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 454661.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.13494_13500del	p.Ser4498ArgfsTer15	frameshift_variant	82/82	ENST00000409508.8
CDCA7L	NM_018719.5	c.*1125_*1131del		3_prime_UTR_variant	10/10	ENST00000406877.8
CDCA7L	NM_001127370.3	c.*1125_*1131del		3_prime_UTR_variant	11/11
CDCA7L	NM_001127371.3	c.*1125_*1131del		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.13494_13500del	p.Ser4498ArgfsTer15	frameshift_variant	82/82	5	NM_001277115.2	P1
CDCA7L	ENST00000406877.8	c.*1125_*1131del		3_prime_UTR_variant	10/10	1	NM_018719.5	P1
CDCA7L	ENST00000356195.9	c.*1125_*1131del		3_prime_UTR_variant	11/11	2
CDCA7L	ENST00000488845.1	n.1647_1653del		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461586 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727066

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 11, 2017

For these reasons, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature. However, this variant occurs with a pathogenic variant (p.Arg1480*) in DNAH11 in an individual with primary ciliary dyskinesia (Invitae). While it is unknown if these two variants are on the same or opposite chromosomes, this observation suggests the c.13494_13500del substitution likely contributes to the cause of disease. This sequence change deletes 7 nucleotide from exon 82 of the DNAH11 mRNA (c.13494_13500del), causing a frameshift at codon 4498. This creates a premature translational stop signal in the last exon of the DNAH11 mRNA (p.Ser4498Argfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acids of the DNAH11 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1212535211; hg19: chr7-21940808;