chr7-21738811-T-C

Position:

• chr7-21738811-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001277115.2(DNAH11):​c.7756T>C​(p.Tyr2586His) variant causes a missense change. The variant allele was found at a frequency of 0.0508 in 1,604,626 control chromosomes in the GnomAD database, including 2,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (132 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2240 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071105957).
• BP6: Variant 7-21738811-T-C is Benign according to our data. Variant chr7-21738811-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 163111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21738811-T-C is described in Lovd as [Benign]. Variant chr7-21738811-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.7756T>C	p.Tyr2586His	missense_variant	47/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.7756T>C	p.Tyr2586His	missense_variant	47/82	5	NM_001277115.2	ENSP00000475939.1
DNAH11	ENST00000605912.1	c.316T>C	p.Tyr106His	missense_variant	2/4	3		ENSP00000476068.1

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5235 AN: 152130 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.00987

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0559

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0374 AC: 8811 AN: 235612 Hom.: 234 AF XY: 0.0377 AC XY: 4789 AN XY: 127106

Gnomad AFR exome AF: 0.00878

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.0000572

Gnomad SAS exome AF: 0.0264

Gnomad FIN exome AF: 0.0416

Gnomad NFE exome AF: 0.0559

Gnomad OTH exome AF: 0.0341

GnomAD4 exome AF: 0.0526 AC: 76332 AN: 1452378 Hom.: 2240 Cov.: 30 AF XY: 0.0516 AC XY: 37214 AN XY: 721364

Gnomad4 AFR exome AF: 0.00762

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0248

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.0283

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0606

Gnomad4 OTH exome AF: 0.0462

GnomAD4 genome AF: 0.0344 AC: 5231 AN: 152248 Hom.: 132 Cov.: 32 AF XY: 0.0327 AC XY: 2433 AN XY: 74438

Gnomad4 AFR AF: 0.00984

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0418

Gnomad4 NFE AF: 0.0559

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0500 Hom.: 348

Bravo AF: 0.0324

TwinsUK AF: 0.0623 AC: 231

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.0152 AC: 66

ESP6500EA AF: 0.0550 AC: 471

ExAC AF: 0.0375 AC: 4542

Asia WGS AF: 0.00751 AC: 26 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Tyr2586His in exon 47 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 5.5% (471/8562) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs2003417). -

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;.;D;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D
MetaRNN	Benign	0.0071	T;T;T;T
MetaSVM	Benign	-0.77	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.7	.;D;.;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	.;D;.;.
Sift4G	Pathogenic	0.0	.;.;.;D
Vest4		0.21
ClinPred		0.053	T
GERP RS		5.4
Varity_R		0.76
gMVP		0.59

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: rs2003417; hg19: chr7-21778429; COSMIC: COSV60985273;