7-21639025-A-G

Position:

• chr7-21639025-A-G

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.4904A>G​(p.Asp1635Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0471 in 1,613,206 control chromosomes in the GnomAD database, including 2,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (240 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1770 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.14

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=0.004967749).
• BP6: Variant 7-21639025-A-G is Benign according to our data. Variant chr7-21639025-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 163105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21639025-A-G is described in Lovd as [Benign]. Variant chr7-21639025-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.4904A>G	p.Asp1635Gly	missense_variant	28/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.4904A>G	p.Asp1635Gly	missense_variant	28/82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.0522 AC: 7933 AN: 152098 Hom.: 241 Cov.: 32

Gnomad AFR AF: 0.0710

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0547

GnomAD3 exomes AF: 0.0443 AC: 10999 AN: 248486 Hom.: 324 AF XY: 0.0446 AC XY: 6016 AN XY: 134814

Gnomad AFR exome AF: 0.0702

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.00323

Gnomad SAS exome AF: 0.0435

Gnomad FIN exome AF: 0.0351

Gnomad NFE exome AF: 0.0495

Gnomad OTH exome AF: 0.0500

GnomAD4 exome AF: 0.0465 AC: 67984 AN: 1460990 Hom.: 1770 Cov.: 30 AF XY: 0.0466 AC XY: 33854 AN XY: 726750

Gnomad4 AFR exome AF: 0.0701

Gnomad4 AMR exome AF: 0.0246

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.00118

Gnomad4 SAS exome AF: 0.0432

Gnomad4 FIN exome AF: 0.0373

Gnomad4 NFE exome AF: 0.0471

Gnomad4 OTH exome AF: 0.0527

GnomAD4 genome AF: 0.0521 AC: 7929 AN: 152216 Hom.: 240 Cov.: 32 AF XY: 0.0505 AC XY: 3761 AN XY: 74418

Gnomad4 AFR AF: 0.0707

Gnomad4 AMR AF: 0.0341

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0464

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0541

Alfa AF: 0.0502 Hom.: 392

Bravo AF: 0.0520

TwinsUK AF: 0.0469 AC: 174

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.0687 AC: 258

ESP6500EA AF: 0.0461 AC: 378

ExAC AF: 0.0452 AC: 5458

Asia WGS AF: 0.0340 AC: 120 AN: 3478

EpiCase AF: 0.0474

EpiControl AF: 0.0445

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	Asp1635Gly in exon 28 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 6.9% (258/3754) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs17144835). -

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	Feb 01, 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	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;.;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.2	.;D;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	.;D;.
Vest4		0.29
ClinPred		0.10	T
GERP RS		5.8
Varity_R		0.82
gMVP		0.65

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: rs17144835; hg19: chr7-21678643; COSMIC: COSV99080605; COSMIC: COSV99080605;