chr7-21861975-G-A

Position:

• chr7-21861975-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001277115.2(DNAH11):​c.11325G>A​(p.Ala3775=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.054 in 1,613,346 control chromosomes in the GnomAD database, including 4,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (525 hom., cov: 32)
  • Exomes 𝑓: 0.054 (4108 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.30

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-21861975-G-A is Benign according to our data. Variant chr7-21861975-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21861975-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.11325G>A	p.Ala3775=	synonymous_variant	69/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.11325G>A	p.Ala3775=	synonymous_variant	69/82	5	NM_001277115.2	ENSP00000475939	P1
DNAH11	ENST00000421290.1	n.508G>A		non_coding_transcript_exon_variant	4/4	4
DNAH11	ENST00000607413.5			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8506 AN: 152120 Hom.: 515 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0458

Gnomad OTH AF: 0.0545

GnomAD3 exomes AF: 0.0915 AC: 22686 AN: 248056 Hom.: 2089 AF XY: 0.0828 AC XY: 11138 AN XY: 134588

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.272

Gnomad ASJ exome AF: 0.0431

Gnomad EAS exome AF: 0.210

Gnomad SAS exome AF: 0.0651

Gnomad FIN exome AF: 0.0719

Gnomad NFE exome AF: 0.0449

Gnomad OTH exome AF: 0.0753

GnomAD4 exome AF: 0.0538 AC: 78670 AN: 1461108 Hom.: 4108 Cov.: 34 AF XY: 0.0535 AC XY: 38913 AN XY: 726802

Gnomad4 AFR exome AF: 0.00795

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.0437

Gnomad4 EAS exome AF: 0.207

Gnomad4 SAS exome AF: 0.0632

Gnomad4 FIN exome AF: 0.0720

Gnomad4 NFE exome AF: 0.0401

Gnomad4 OTH exome AF: 0.0552

GnomAD4 genome AF: 0.0560 AC: 8524 AN: 152238 Hom.: 525 Cov.: 32 AF XY: 0.0605 AC XY: 4501 AN XY: 74426

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.0710

Gnomad4 FIN AF: 0.0706

Gnomad4 NFE AF: 0.0459

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0512 Hom.: 776

Bravo AF: 0.0644

Asia WGS AF: 0.144 AC: 501 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala3775Ala in exon 69 of DNAH11: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 4.3% (363/8394) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12666072). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.056
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs12666072; hg19: chr7-21901593; COSMIC: COSV60946338; COSMIC: COSV60946338;