7-21543246-A-T

Variant names:

• chr7-21543246-A-T
• rs1162526607
• NM_001277115.2:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_001277115.2(DNAH11):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,380,104 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102
• Publications: 0 publications found

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]

DNAH11 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 68 codons. Genomic position: 21543447. Lost 0.015 part of the original CDS.
• PS1: Another start lost variant in NM_001277115.2 (DNAH11) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277115.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 82	NP_001264044.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 82	ENSP00000475939.1
	DNAH11	ENST00000607050.1	TSL:3	n.-200A>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1380104 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 678936

African (AFR) AF: 0.00 AC: 0 AN: 31062

American (AMR) AF: 0.00 AC: 0 AN: 34280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24760

East Asian (EAS) AF: 0.00 AC: 0 AN: 35428

South Asian (SAS) AF: 0.00 AC: 0 AN: 78282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4074

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1071056

Other (OTH) AF: 0.00 AC: 0 AN: 57106

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.42	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.10
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.51
MutPred		0.66		Gain of stability (P = 0.0061)
MVP		0.17
ClinPred		0.53	D
GERP RS		2.3
PromoterAI		-0.010	Neutral
Varity_R		0.32
gMVP		0.18
Mutation Taster		=67/133	disease causing

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

Other links and lift over

dbSNP: rs1162526607; hg19: chr7-21582864;