rs1254126467

chr7-21901216-T-TGGGTTCTGGCTG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_001277115.2(DNAH11):c.13515_13526dup(p.Leu4507_Val4510dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.48

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: Nonframeshift variant in NON repetitive region in NM_001277115.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-21901216-T-TGGGTTCTGGCTG is Pathogenic according to our data. Variant chr7-21901216-T-TGGGTTCTGGCTG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525412.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.13515_13526dup	p.Leu4507_Val4510dup	inframe_insertion	82/82	ENST00000409508.8
CDCA7L	NM_018719.5	c.*1105_*1106insCAGCCAGAACCC		3_prime_UTR_variant	10/10	ENST00000406877.8
CDCA7L	NM_001127370.3	c.*1105_*1106insCAGCCAGAACCC		3_prime_UTR_variant	11/11
CDCA7L	NM_001127371.3	c.*1105_*1106insCAGCCAGAACCC		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.13515_13526dup	p.Leu4507_Val4510dup	inframe_insertion	82/82	5	NM_001277115.2	P1
CDCA7L	ENST00000406877.8	c.*1105_*1106insCAGCCAGAACCC		3_prime_UTR_variant	10/10	1	NM_018719.5	P1
CDCA7L	ENST00000356195.9	c.*1105_*1106insCAGCCAGAACCC		3_prime_UTR_variant	11/11	2
CDCA7L	ENST00000488845.1	n.1627_1628insCAGCCAGAACCC		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150656 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461562 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727044

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150656 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73578

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2023

- -

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2018

This variant, c.13515_13526dupGGTTCTGGCTGG, results in the insertion of 4 amino acids to the DNAH11 protein (p.Leu4507_Val4510dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with primary ciliary dyskinesia (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs1254126467; hg19: chr7-21940834;