rs374549012

chr7-21818285-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001277115.2(DNAH11):c.10637C>T(p.Thr3546Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,611,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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. T3546T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (1 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0580

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13775277).
• BP6: Variant 7-21818285-C-T is Benign according to our data. Variant chr7-21818285-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567254.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr7-21818285-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.10637C>T	p.Thr3546Met	missense_variant	65/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.10637C>T	p.Thr3546Met	missense_variant	65/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000767 AC: 19 AN: 247758 Hom.: 0 AF XY: 0.0000372 AC XY: 5 AN XY: 134440

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000800

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000514 AC: 75 AN: 1459678 Hom.: 1 Cov.: 31 AF XY: 0.0000496 AC XY: 36 AN XY: 726092

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74360

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000775 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000544 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000911 AC: 11

EpiCase AF: 0.0000547

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 13, 2023	The c.10637C>T (p.T3546M) alteration is located in exon 65 (coding exon 65) of the DNAH11 gene. This alteration results from a C to T substitution at nucleotide position 10637, causing the threonine (T) at amino acid position 3546 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 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	14
Dann	Uncertain	1.0
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	0.65	D
PrimateAI	Benign	0.31	T
Vest4		0.39
MVP		0.13
ClinPred		0.59	D
GERP RS		3.4
Varity_R		0.067
gMVP		0.39

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: rs374549012; hg19: chr7-21857903; COSMIC: COSV100175986;