rs72657372

Variant names:

• chr7-21765505-G-A
• rs72657372
• NM_001277115.2:c.9018G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001277115.2(DNAH11):​c.9018G>A​(p.Thr3006Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,613,764 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (35 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (58 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.867
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 7-21765505-G-A is Benign according to our data. Variant chr7-21765505-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238939.
• BP7: Synonymous conserved (PhyloP=-0.867 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (2064/152150) while in subpopulation AFR AF = 0.0477 (1980/41512). AF 95% confidence interval is 0.0459. There are 35 homozygotes in GnomAd4. There are 980 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.9018G>A	p.Thr3006Thr	synonymous	Exon 55 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.9018G>A	p.Thr3006Thr	synonymous	Exon 55 of 82	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2046 AN: 152032 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00720

GnomAD2 exomes AF: 0.00347 AC: 864 AN: 248978 AF XY: 0.00269

Gnomad AFR exome AF: 0.0484

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000886

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.00141 AC: 2065 AN: 1461614 Hom.: 58 Cov.: 31 AF XY: 0.00120 AC XY: 873 AN XY: 727090

African (AFR) AF: 0.0505 AC: 1689 AN: 33472

American (AMR) AF: 0.00275 AC: 123 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111808

Other (OTH) AF: 0.00301 AC: 182 AN: 60368

GnomAD4 genome AF: 0.0136 AC: 2064 AN: 152150 Hom.: 35 Cov.: 31 AF XY: 0.0132 AC XY: 980 AN XY: 74374

African (AFR) AF: 0.0477 AC: 1980 AN: 41512

American (AMR) AF: 0.00412 AC: 63 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67994

Other (OTH) AF: 0.00712 AC: 15 AN: 2106

Alfa AF: 0.00471 Hom.: 52

Bravo AF: 0.0152

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Primary ciliary dyskinesia (3)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.1
DANN	Benign	0.86
PhyloP100		-0.87
Mutation Taster		=100/0	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: rs72657372; hg19: chr7-21805123;