rs375341444

chr7-21698185-C-T

Variant summary

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

The NM_001277115.2(DNAH11):c.6152C>T(p.Thr2051Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2051T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.693

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=0.24456584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.6152C>T	p.Thr2051Met	missense_variant	36/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.6152C>T	p.Thr2051Met	missense_variant	36/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000442 AC: 11 AN: 248946 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135042

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461296 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 726910

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74294

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000579 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2021	The c.6152C>T (p.T2051M) alteration is located in exon 36 (coding exon 36) of the DNAH11 gene. This alteration results from a C to T substitution at nucleotide position 6152, causing the threonine (T) at amino acid position 2051 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 13, 2017

The p.Thr2051Met variant in DNAH11 has not been previously reported in individua ls with pulmonary disease, but has been identified in 5/66626 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs375341444). This variant has been identified in ClinVar (Variant ID: 35964 0). Computational prediction tools and conservation analysis suggest that the p. Thr2051Met variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr2051Met variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	0.83	D
PrimateAI	Benign	0.30	T
Vest4		0.47
MVP		0.36
ClinPred		0.32	T
GERP RS		2.5
Varity_R		0.057
gMVP		0.24

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: rs375341444; hg19: chr7-21737803;