chr7-21558875-A-T

Variant names:

• chr7-21558875-A-T
• rs201793112
• NM_001277115.2:c.569A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001277115.2(DNAH11):​c.569A>T​(p.Tyr190Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,609,028 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. Y190Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (4 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.466
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02276218).
• BP6: Variant 7-21558875-A-T is Benign according to our data. Variant chr7-21558875-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 359596.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.569A>T	p.Tyr190Phe	missense	Exon 3 of 82	NP_001264044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.569A>T	p.Tyr190Phe	missense	Exon 3 of 82	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000358 AC: 86 AN: 240198 AF XY: 0.000408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000941

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.000353 AC: 514 AN: 1456782 Hom.: 4 Cov.: 31 AF XY: 0.000407 AC XY: 295 AN XY: 724090

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85100

European-Finnish (FIN) AF: 0.000470 AC: 25 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000425 AC: 471 AN: 1109410

Other (OTH) AF: 0.000299 AC: 18 AN: 60174

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000506 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000736 AC: 6

ExAC AF: 0.000356 AC: 43

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Primary ciliary dyskinesia (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.1
DANN	Benign	0.89
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.47
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.055
Sift	Uncertain	0.023	D
Polyphen		0.011	B
Vest4		0.19
MVP		0.088
ClinPred		0.035	T
GERP RS		-9.1
Varity_R		0.052
gMVP		0.083
Mutation Taster		=93/7	polymorphism

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: rs201793112; hg19: chr7-21598493; COSMIC: COSV99071959; COSMIC: COSV99071959;