rs368833367

chr7-21842537-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001277115.2(DNAH11):c.10692-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,611,764 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).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001908
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.262

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-21842537-C-T is Benign according to our data. Variant chr7-21842537-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257847.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr7-21842537-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.10692-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.10692-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000234 AC: 58 AN: 247564 Hom.: 0 AF XY: 0.000261 AC XY: 35 AN XY: 134326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000402

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000295 AC: 431 AN: 1459658 Hom.: 0 Cov.: 30 AF XY: 0.000311 AC XY: 226 AN XY: 726026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74290

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000244 Hom.: 0

Bravo AF: 0.000321

EpiCase AF: 0.000383

EpiControl AF: 0.000476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.8
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs368833367; hg19: chr7-21882155;