rs200216579

Positions:

• chr7-21617747-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001277115.2(DNAH11):​c.4224G>T​(p.Arg1408Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,606,314 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0400

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-21617747-G-T is Benign according to our data. Variant chr7-21617747-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 454674.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.4224G>T	p.Arg1408Ser	missense_variant	23/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.4224G>T	p.Arg1408Ser	missense_variant	23/82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000174 AC: 42 AN: 242002 Hom.: 0 AF XY: 0.000168 AC XY: 22 AN XY: 131318

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000865

GnomAD4 exome AF: 0.000307 AC: 447 AN: 1454122 Hom.: 1 Cov.: 31 AF XY: 0.000303 AC XY: 219 AN XY: 722830

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: 0.0000751

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.000350

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74336

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000149 AC: 18

EpiCase AF: 0.000274

EpiControl AF: 0.000299

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 10, 2023	The c.4224G>T (p.R1408S) alteration is located in exon 23 (coding exon 23) of the DNAH11 gene. This alteration results from a G to T substitution at nucleotide position 4224, causing the arginine (R) at amino acid position 1408 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;.;D
Eigen	Benign	0.0087
Eigen_PC	Benign	-0.034
FATHMM_MKL	Benign	0.45	N
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.45	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.1	.;D;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	.;D;.
Vest4		0.74
MutPred		0.82		Loss of MoRF binding (P = 0.0225);Loss of MoRF binding (P = 0.0225);.;
MVP		0.47
ClinPred		0.60	D
GERP RS		1.1
Varity_R		0.84
gMVP		0.67

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: rs200216579; hg19: chr7-21657365;