rs10247099

Variant names:

• chr7-21735621-A-G
• rs10247099
• NM_001277115.2:c.7441-19A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-21735621-A-G
• chr7-21735621-A-T

Variant summary

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

The ENST00000409508.8(DNAH11):​c.7441-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,559,458 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0072 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (21 hom.)
• Consequence: DNAH11 ENST00000409508.8 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.58
• Publications: 0 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-21735621-A-G is Benign according to our data. Variant chr7-21735621-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257928.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00718 (1093/152266) while in subpopulation AFR AF = 0.0254 (1054/41554). AF 95% confidence interval is 0.0241. There are 13 homozygotes in GnomAd4. There are 511 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000409508.8. 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.7441-19A>G		intron	N/A	NP_001264044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.7441-19A>G		intron	N/A	ENSP00000475939.1
	DNAH11	ENST00000605912.1	TSL:3	c.-19A>G		upstream_gene	N/A	ENSP00000476068.1

Frequencies

GnomAD3 genomes AF: 0.00716 AC: 1090 AN: 152148 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00189 AC: 323 AN: 171316 AF XY: 0.00171

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000340

Gnomad NFE exome AF: 0.0000578

Gnomad OTH exome AF: 0.000425

GnomAD4 exome AF: 0.000824 AC: 1159 AN: 1407192 Hom.: 21 Cov.: 31 AF XY: 0.000730 AC XY: 507 AN XY: 694928

African (AFR) AF: 0.0311 AC: 998 AN: 32098

American (AMR) AF: 0.00108 AC: 39 AN: 36198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 36802

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80316

European-Finnish (FIN) AF: 0.000278 AC: 14 AN: 50284

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5700

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1082140

Other (OTH) AF: 0.00159 AC: 93 AN: 58406

GnomAD4 genome AF: 0.00718 AC: 1093 AN: 152266 Hom.: 13 Cov.: 33 AF XY: 0.00686 AC XY: 511 AN XY: 74460

African (AFR) AF: 0.0254 AC: 1054 AN: 41554

American (AMR) AF: 0.00177 AC: 27 AN: 15296

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00222 Hom.: 1

Bravo AF: 0.00829

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.079
DANN	Benign	0.31
PhyloP100		-1.6
BranchPoint Hunter		3.0
PromoterAI		0.025	Neutral
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: rs10247099; hg19: chr7-21775239;