rs141572016

Positions:

• chr7-21655820-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):​c.4945-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,609,516 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004946
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.701

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-21655820-T-C is Benign according to our data. Variant chr7-21655820-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257901.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000389 (567/1457188) while in subpopulation MID AF= 0.0108 (62/5760). AF 95% confidence interval is 0.00862. There are 3 homozygotes in gnomad4_exome. There are 292 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.4945-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.4945-12T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001277115.2	ENSP00000475939	P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000492 AC: 120 AN: 244032 Hom.: 0 AF XY: 0.000568 AC XY: 75 AN XY: 132116

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.000590

Gnomad ASJ exome AF: 0.000807

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.000389 AC: 567 AN: 1457188 Hom.: 3 Cov.: 32 AF XY: 0.000403 AC XY: 292 AN XY: 724502

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.000609

Gnomad4 ASJ exome AF: 0.000730

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000444

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000304

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000886 Hom.: 0

Bravo AF: 0.000302

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 03, 2017	c.4945-12T>C in intron 28 of DNAH11: This variant is not expected to have clinic al significance because a T>C change at this position does not diverge from the splice consensus sequence and is therefore unlikely to impact splicing. It has b een identified in 0.1% (48/53352) of European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs141572016). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.50
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.030		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: rs141572016; hg19: chr7-21695438;