7-21635864-A-T

Variant names:

• chr7-21635864-A-T
• rs62447794
• NM_001277115.2:c.4501-7A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):​c.4501-7A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00727 in 1,599,572 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (49 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_region, intron
• Scores: Splicing: ADA: 0.0002229
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.142
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-21635864-A-T is Benign according to our data. Variant chr7-21635864-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220718.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00431 (656/152246) while in subpopulation NFE AF = 0.00765 (520/68018). AF 95% confidence interval is 0.0071. There are 1 homozygotes in GnomAd4. There are 324 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 49 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.4501-7A>T		splice_region intron	N/A	NP_001264044.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.4501-7A>T		splice_region intron	N/A	ENSP00000475939.1
	DNAH11	ENST00000465593.1	TSL:2	n.527-7A>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 656 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00423 AC: 973 AN: 229952 AF XY: 0.00431

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00775

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00759 AC: 10980 AN: 1447326 Hom.: 49 Cov.: 30 AF XY: 0.00728 AC XY: 5225 AN XY: 718196

African (AFR) AF: 0.00151 AC: 50 AN: 33136

American (AMR) AF: 0.00121 AC: 52 AN: 43070

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 63 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.000584 AC: 49 AN: 83898

European-Finnish (FIN) AF: 0.00360 AC: 187 AN: 51984

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5732

European-Non Finnish (NFE) AF: 0.00937 AC: 10353 AN: 1104330

Other (OTH) AF: 0.00374 AC: 224 AN: 59926

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00435 AC XY: 324 AN XY: 74422

African (AFR) AF: 0.00115 AC: 48 AN: 41560

American (AMR) AF: 0.000851 AC: 13 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00765 AC: 520 AN: 68018

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00599 Hom.: 1

Bravo AF: 0.00455

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.044
SpliceAI score (max)		0.020		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: rs62447794; hg19: chr7-21675482;