rs17144788

Positions:

• chr7-21615207-A-G

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.3946A>G​(p.Met1316Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,536 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0190

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=0.0023182034).
• BP6: Variant 7-21615207-A-G is Benign according to our data. Variant chr7-21615207-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 238914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21615207-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1698/152330) while in subpopulation AFR AF= 0.0382 (1589/41578). AF 95% confidence interval is 0.0367. There are 21 homozygotes in gnomad4. There are 784 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.3946A>G	p.Met1316Val	missense_variant	21/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.3946A>G	p.Met1316Val	missense_variant	21/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1696 AN: 152212 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00291 AC: 722 AN: 248388 Hom.: 11 AF XY: 0.00215 AC XY: 289 AN XY: 134728

Gnomad AFR exome AF: 0.0414

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00113 AC: 1654 AN: 1461206 Hom.: 28 Cov.: 30 AF XY: 0.000999 AC XY: 726 AN XY: 726864

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.0111 AC: 1698 AN: 152330 Hom.: 21 Cov.: 32 AF XY: 0.0105 AC XY: 784 AN XY: 74498

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00260 Hom.: 7

Bravo AF: 0.0131

ESP6500AA AF: 0.0301 AC: 111

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00341 AC: 412

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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	Feb 21, 2013	Met1316Val in exon 21 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 3.0% (111/3684) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs17144788). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 28, 2017	- -

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	0.096
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.97
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.85	D;D;D
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.78	N
PrimateAI	Benign	0.38	T
Polyphen		0.012	.;.;B
Vest4		0.17
MVP		0.35
ClinPred		0.0048	T
GERP RS		2.9
Varity_R		0.096
gMVP		0.38

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: rs17144788; hg19: chr7-21654825;