rs114257197

chr7-21854453-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001277115.2(DNAH11):c.11200A>C(p.Lys3734Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,612,972 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (19 hom.)
• Consequence: DNAH11 NM_001277115.2 missense, splice_region
• Scores: Splicing: ADA: 0.8226
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.48

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 -16 ACMG points.

• BP6: Variant 7-21854453-A-C is Benign according to our data. Variant chr7-21854453-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 227316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00713 (1085/152234) while in subpopulation AFR AF= 0.0246 (1023/41538). AF 95% confidence interval is 0.0234. There are 12 homozygotes in gnomad4. There are 505 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.11200A>C	p.Lys3734Gln	missense_variant, splice_region_variant	68/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.11200A>C	p.Lys3734Gln	missense_variant, splice_region_variant	68/82	5	NM_001277115.2	P1
DNAH11	ENST00000421290.1	n.383A>C		splice_region_variant, non_coding_transcript_exon_variant	3/4	4
DNAH11	ENST00000607413.5	n.463A>C		splice_region_variant, non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 1078 AN: 152118 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00190 AC: 473 AN: 248656 Hom.: 3 AF XY: 0.00145 AC XY: 196 AN XY: 134900

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.000847 AC: 1237 AN: 1460738 Hom.: 19 Cov.: 34 AF XY: 0.000738 AC XY: 536 AN XY: 726568

Gnomad4 AFR exome AF: 0.0266

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000124

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00713 AC: 1085 AN: 152234 Hom.: 12 Cov.: 32 AF XY: 0.00678 AC XY: 505 AN XY: 74436

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00136 Hom.: 7

Bravo AF: 0.00815

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0237 AC: 85

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00240 AC: 290

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000548

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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	May 10, 2018	The p.Lys3734Gln in exon 68 of DNAH11 is classified as benign because it has bee n identified in 2.5% (607/23998) of African chromosomes, including 4 homozygotes , by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs114257197). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 19, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0091	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
Vest4		0.46
MVP		0.66
ClinPred		0.013	T
GERP RS		5.7
Varity_R		0.42
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.030		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: rs114257197; hg19: chr7-21894071;