7-21884408-C-T

Variant names:

• chr7-21884408-C-T
• rs764262245
• NM_001277115.2:c.12505C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001277115.2(DNAH11):​c.12505C>T​(p.Leu4169Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,444,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L4169L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.05492
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.119
• 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]

DNAH11 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 7-21884408-C-T is Benign according to our data. Variant chr7-21884408-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257861.
• BP7: Synonymous conserved (PhyloP=0.119 with no splicing effect.

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.12505C>T	p.Leu4169Leu	splice_region synonymous	Exon 76 of 82	NP_001264044.1	Q96DT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.12505C>T	p.Leu4169Leu	splice_region synonymous	Exon 76 of 82	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000170 AC: 4 AN: 234860 AF XY: 0.0000314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000213

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1444984 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 718114

African (AFR) AF: 0.00 AC: 0 AN: 32846

American (AMR) AF: 0.00 AC: 0 AN: 41268

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 3 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 39290

South Asian (SAS) AF: 0.0000367 AC: 3 AN: 81786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000633 AC: 7 AN: 1105702

Other (OTH) AF: 0.0000502 AC: 3 AN: 59780

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not specified (1)
-	1	-	Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.9
DANN	Benign	0.81
PhyloP100		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.055
dbscSNV1_RF	Benign	0.27
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

Other links and lift over

dbSNP: rs764262245; hg19: chr7-21924026; COSMIC: COSV60979662;