rs143362381

Positions:

• chr7-21901198-G-A

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.13495G>A​(p.Glu4499Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,613,662 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (43 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.04

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]

CDCA7L (HGNC:30777): (cell division cycle associated 7 like) Acts upstream of or within positive regulation of cell population proliferation. Located in cytosol; fibrillar center; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CDCA7L (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002060622).
• BP6: Variant 7-21901198-G-A is Benign according to our data. Variant chr7-21901198-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21901198-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00363 (5312/1461600) while in subpopulation MID AF= 0.00433 (25/5768). AF 95% confidence interval is 0.00308. There are 43 homozygotes in gnomad4_exome. There are 2634 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.13495G>A	p.Glu4499Lys	missense_variant	82/82	ENST00000409508.8	NP_001264044.1
CDCA7L	NM_018719.5	c.*1124C>T		3_prime_UTR_variant	10/10	ENST00000406877.8	NP_061189.2
CDCA7L	NM_001127370.3	c.*1124C>T		3_prime_UTR_variant	11/11		NP_001120842.1
CDCA7L	NM_001127371.3	c.*1124C>T		3_prime_UTR_variant	9/9		NP_001120843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.13495G>A	p.Glu4499Lys	missense_variant	82/82	5	NM_001277115.2	ENSP00000475939.1
CDCA7L	ENST00000406877	c.*1124C>T		3_prime_UTR_variant	10/10	1	NM_018719.5	ENSP00000383986.3
CDCA7L	ENST00000356195	c.*1124C>T		3_prime_UTR_variant	11/11	2		ENSP00000348523.5
CDCA7L	ENST00000488845.1	n.1646C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 604 AN: 151946 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00314

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00458 AC: 1131 AN: 247058 Hom.: 18 AF XY: 0.00450 AC XY: 604 AN XY: 134214

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00217

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.00330

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00363 AC: 5312 AN: 1461600 Hom.: 43 Cov.: 33 AF XY: 0.00362 AC XY: 2634 AN XY: 727068

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00166

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.0232

Gnomad4 NFE exome AF: 0.00316

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00397 AC: 604 AN: 152062 Hom.: 7 Cov.: 33 AF XY: 0.00518 AC XY: 385 AN XY: 74340

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.00314

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.00297

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00247 Hom.: 3

Bravo AF: 0.00193

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00253 AC: 21

ExAC AF: 0.00400 AC: 484

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely 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	Dec 09, 2015	p.Glu4499Lys in exon 82 of DNAH11: This variant has been identified in 2.48% (1 64/6614) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs143362381). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	DNAH11: BP4 -

Primary ciliary dyskinesia 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.1
DANN	Benign	0.66
DEOGEN2	Benign	0.013	.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.52	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	3.1	.;N;.
REVEL	Benign	0.032
Sift	Benign	1.0	.;T;.
Vest4		0.16
MVP		0.085
ClinPred		0.0019	T
GERP RS		0.46
Varity_R		0.025
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143362381; hg19: chr7-21940816; COSMIC: COSV99050047; COSMIC: COSV99050047;