rs144106494

Variant names:

• chr7-21658888-C-T
• rs144106494
• NM_001277115.2:c.5185C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001277115.2(DNAH11):​c.5185C>T​(p.Pro1729Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,609,564 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1729H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.28
• Publications: 3 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009319246).
• BP6: Variant 7-21658888-C-T is Benign according to our data. Variant chr7-21658888-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 188238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00325 (494/152078) while in subpopulation AFR AF = 0.0112 (464/41492). AF 95% confidence interval is 0.0103. There are 3 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.5185C>T	p.Pro1729Ser	missense	Exon 30 of 82	NP_001264044.1	Q96DT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.5185C>T	p.Pro1729Ser	missense	Exon 30 of 82	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 151960 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000691 AC: 167 AN: 241834 AF XY: 0.000519

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000300 AC: 437 AN: 1457486 Hom.: 3 Cov.: 31 AF XY: 0.000247 AC XY: 179 AN XY: 724498

African (AFR) AF: 0.0113 AC: 376 AN: 33408

American (AMR) AF: 0.000453 AC: 20 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1110086

Other (OTH) AF: 0.000531 AC: 32 AN: 60210

GnomAD4 genome AF: 0.00325 AC: 494 AN: 152078 Hom.: 3 Cov.: 31 AF XY: 0.00323 AC XY: 240 AN XY: 74348

African (AFR) AF: 0.0112 AC: 464 AN: 41492

American (AMR) AF: 0.00131 AC: 20 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67982

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00371

ESP6500AA AF: 0.00729 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000804 AC: 97

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.3
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.15
Sift	Benign	0.080	T
Vest4		0.41
MVP		0.48
ClinPred		0.056	T
GERP RS		5.9
Varity_R		0.091
gMVP		0.21
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144106494; hg19: chr7-21698506;