rs1554294478

Variant names:

• chr7-21901224-GGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCT-G
• rs1554294478
• NM_001277115.2:c.13531_*36delGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP5_Moderate

The NM_001277115.2(DNAH11):​c.13531_*36delGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTG​(p.Ala4511_Ter4517del) variant causes a stop lost, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,178 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 stop_lost, conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.77
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Stoplost variant in NM_001277115.2 Downstream stopcodon found after 55 codons.
• PP5: Variant 7-21901224-GGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCT-G is Pathogenic according to our data. Variant chr7-21901224-GGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6476.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277115.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.13531_*36delGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTG	p.Ala4511_Ter4517del	stop_lost conservative_inframe_deletion	Exon 82 of 82	NP_001264044.1	Q96DT5
	DNAH11	NM_001277115.2	MANE Select	c.13531_*36delGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTG		3_prime_UTR	Exon 82 of 82	NP_001264044.1	Q96DT5
	CDCA7L	NM_018719.5	MANE Select	c.*1041_*1097delAGAGGCTAGAGGAATGCCAGTGTTACCTTACGCTTCTAGAAGCAGAGCCACTCCAGC		3_prime_UTR	Exon 10 of 10	NP_061189.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.13531_*36delGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTG	p.Ala4511_Ter4517del	stop_lost conservative_inframe_deletion	Exon 82 of 82	ENSP00000475939.1	Q96DT5
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.13531_*36delGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTG		3_prime_UTR	Exon 82 of 82	ENSP00000475939.1	Q96DT5
	CDCA7L	ENST00000406877.8	TSL:1 MANE Select	c.*1041_*1097delAGAGGCTAGAGGAATGCCAGTGTTACCTTACGCTTCTAGAAGCAGAGCCACTCCAGC		3_prime_UTR	Exon 10 of 10	ENSP00000383986.3	Q96GN5-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461178 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726864

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111536

Other (OTH) AF: 0.00 AC: 0 AN: 60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Primary ciliary dyskinesia 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=27/173	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554294478; hg19: chr7-21940842;