rs72657369

Positions:

• chr7-21749774-G-A
• chr7-21749774-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_001277115.2(DNAH11):​c.8770G>A​(p.Val2924Met) variant causes a missense change. The variant allele was found at a frequency of 0.000154 in 1,613,772 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.76

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15356037).
• BP6: Variant 7-21749774-G-A is Benign according to our data. Variant chr7-21749774-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.8770G>A	p.Val2924Met	missense_variant	53/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.8770G>A	p.Val2924Met	missense_variant	53/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000137 AC: 34 AN: 249038 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135096

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461618 Hom.: 1 Cov.: 30 AF XY: 0.000144 AC XY: 105 AN XY: 727092

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74312

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.000709

EpiControl AF: 0.000416

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2022	This alteration is classified as likely 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 specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 27, 2017

p.Val2924Met in exon 53 of DNAH11: This variant is not expected to have clinica l significance because the valine (Val) residue at this position is not well con served across evolutionarily distant species, and the variant residue (Met) has been identified in five mammalian species (gorilla, Rhesus macaque, crab-eating macaque, baboon and green monkey). It has been identified in 32/126528 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org; dbSNP rs72657369). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
Vest4		0.42
MVP		0.28
ClinPred		0.16	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.36

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: rs72657369; hg19: chr7-21789392;