rs72657315

chr7-21619127-A-Gchr7-21619127-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001277115.2(DNAH11):c.4282A>G(p.Thr1428Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00242 in 1,613,654 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (27 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.18

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=0.009599686).
• BP6: Variant 7-21619127-A-G is Benign according to our data. Variant chr7-21619127-A-G is described in ClinVar as [Benign]. Clinvar id is 238917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21619127-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00242 (3534/1461358) while in subpopulation MID AF= 0.0222 (128/5764). AF 95% confidence interval is 0.0191. There are 27 homozygotes in gnomad4_exome. There are 1904 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.4282A>G	p.Thr1428Ala	missense_variant	24/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.4282A>G	p.Thr1428Ala	missense_variant	24/82	5	NM_001277115.2	P1
DNAH11	ENST00000465593.1	n.308A>G		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152178 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00362 AC: 900 AN: 248940 Hom.: 6 AF XY: 0.00387 AC XY: 523 AN XY: 135052

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00273

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00402

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00645

GnomAD4 exome AF: 0.00242 AC: 3534 AN: 1461358 Hom.: 27 Cov.: 30 AF XY: 0.00262 AC XY: 1904 AN XY: 726968

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.0378

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00415

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.00509

GnomAD4 genome AF: 0.00241 AC: 367 AN: 152296 Hom.: 2 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74464

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00367 Hom.: 5

Bravo AF: 0.00265

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000538 AC: 2

ESP6500EA AF: 0.00280 AC: 23

ExAC AF: 0.00334 AC: 403

EpiCase AF: 0.00371

EpiControl AF: 0.00356

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DNAH11: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2020	- -

not specified Benign:1

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

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
Vest4		0.38
MVP		0.41
ClinPred		0.071	T
GERP RS		2.9
Varity_R		0.26
gMVP		0.44

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: rs72657315; hg19: chr7-21658745;