rs72657374

chr7-21765597-G-Achr7-21765597-G-Cchr7-21765597-G-T

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.9102+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,548,870 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 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 0.015 (18 hom., cov: 31)
  • Exomes 𝑓: 0.016 (260 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001321
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.150

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=-0.7).
• BP6: Variant 7-21765597-G-A is Benign according to our data. Variant chr7-21765597-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178729.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2119/144746) while in subpopulation NFE AF= 0.0186 (1232/66088). AF 95% confidence interval is 0.0178. There are 18 homozygotes in gnomad4. There are 951 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.9102+8G>A		splice_region_variant, intron_variant		ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.9102+8G>A		splice_region_variant, intron_variant		5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2119 AN: 144622 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0113

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00789

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00432

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.0197

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0174

GnomAD3 exomes AF: 0.0121 AC: 2495 AN: 205850 Hom.: 25 AF XY: 0.0123 AC XY: 1358 AN XY: 110820

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.00970

Gnomad EAS exome AF: 0.000126

Gnomad SAS exome AF: 0.00526

Gnomad FIN exome AF: 0.00932

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0164 AC: 23045 AN: 1404124 Hom.: 260 Cov.: 32 AF XY: 0.0160 AC XY: 11141 AN XY: 695524

Gnomad4 AFR exome AF: 0.0100

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.0000799

Gnomad4 SAS exome AF: 0.00593

Gnomad4 FIN exome AF: 0.00837

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0146 AC: 2119 AN: 144746 Hom.: 18 Cov.: 31 AF XY: 0.0135 AC XY: 951 AN XY: 70242

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.0162

Gnomad4 ASJ AF: 0.00789

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00432

Gnomad4 FIN AF: 0.00801

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0172

Alfa AF: 0.0109 Hom.: 6

Bravo AF: 0.0149

Asia WGS AF: 0.00202 AC: 8 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	9102+8G>A in intron 55 of DNAH11: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 1.8% (155/8422) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs72657374). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 03, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	2.0
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0020
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: rs72657374; hg19: chr7-21805215; COSMIC: COSV60964567;