7-21789325-A-C

Position:

• chr7-21789325-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001277115.2(DNAH11):​c.10009A>C​(p.Ile3337Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000564 in 1,417,256 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3337V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15606427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.10009A>C	p.Ile3337Leu	missense_variant	61/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.10009A>C	p.Ile3337Leu	missense_variant	61/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000564 AC: 8 AN: 1417256 Hom.: 0 Cov.: 30 AF XY: 0.00000285 AC XY: 2 AN XY: 700606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000735

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2013

Variant classified as Uncertain Significance - Favor Benign. The Ile3337Leu vari ant in DNAH11 has not been previously identified in individuals with pulmonary d isease or in large population studies. Isoleucine (Ile) at position 3337 is poor ly conserved in evolution and at least 1 mammal (armadillo) carries the variant amino acid, raising the possibility that this change may be tolerated. Additiona l computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen 2, and SIFT) also suggest that this variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. In summary, the lack of evolutionary conservation suggests that this variant may be more lik ely benign, but additional information is needed to fully assess its clinical si gnificance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.26	.;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.56	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	.;N;.
REVEL	Benign	0.19
Sift	Benign	0.41	.;T;.
Vest4		0.30
MutPred		0.50		Gain of disorder (P = 0.0405);Gain of disorder (P = 0.0405);.;
MVP		0.38
ClinPred		0.24	T
GERP RS		1.1
Varity_R		0.19
gMVP		0.26

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: rs145645790; hg19: chr7-21828943;