rs1254126467

Variant names:

• chr7-21901216-T-TGGGTTCTGGCTG
• rs1254126467
• NM_001277115.2:c.13515_13526dupGGTTCTGGCTGG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP3 PP5

The NM_001277115.2(DNAH11):​c.13515_13526dupGGTTCTGGCTGG​(p.Gly4509_Val4510insValLeuAlaGly) variant causes a disruptive 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.48
• Publications: 0 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: 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 VariationId is 525412.

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.13515_13526dupGGTTCTGGCTGG	p.Gly4509_Val4510insValLeuAlaGly	disruptive_inframe_insertion	Exon 82 of 82	NP_001264044.1	Q96DT5
	CDCA7L	NM_018719.5	MANE Select	c.*1094_*1105dupCAGCCAGAACCC		3_prime_UTR	Exon 10 of 10	NP_061189.2
	CDCA7L	NM_001127370.3		c.*1094_*1105dupCAGCCAGAACCC		3_prime_UTR	Exon 11 of 11	NP_001120842.1	Q96GN5-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.13515_13526dupGGTTCTGGCTGG	p.Gly4509_Val4510insValLeuAlaGly	disruptive_inframe_insertion	Exon 82 of 82	ENSP00000475939.1	Q96DT5
	CDCA7L	ENST00000406877.8	TSL:1 MANE Select	c.*1094_*1105dupCAGCCAGAACCC		3_prime_UTR	Exon 10 of 10	ENSP00000383986.3	Q96GN5-1
	CDCA7L	ENST00000934293.1		c.*1094_*1105dupCAGCCAGAACCC		3_prime_UTR	Exon 10 of 10	ENSP00000604352.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111794

Other (OTH) AF: 0.00 AC: 0 AN: 60368

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

African (AFR) AF: 0.00 AC: 0 AN: 41060

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67422

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Primary ciliary dyskinesia 7 (2)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=57/43	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1254126467; hg19: chr7-21940834;