rs185794149

Variant names:

• chr7-21873480-C-T
• rs185794149
• NM_001277115.2:c.12174C>T

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.12174C>T​(p.Ala4058Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,613,888 control chromosomes in the GnomAD database, including 3 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 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00082 (3 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.973
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 7-21873480-C-T is Benign according to our data. Variant chr7-21873480-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 359683.
• BP7: Synonymous conserved (PhyloP=-0.973 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0011 (168/152240) while in subpopulation AMR AF = 0.00379 (58/15284). AF 95% confidence interval is 0.00301. There are 0 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.12174C>T	p.Ala4058Ala	synonymous	Exon 74 of 82	NP_001264044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.12174C>T	p.Ala4058Ala	synonymous	Exon 74 of 82	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00111 AC: 275 AN: 248858 AF XY: 0.00101

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00657

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000896

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.000822 AC: 1202 AN: 1461648 Hom.: 3 Cov.: 31 AF XY: 0.000831 AC XY: 604 AN XY: 727104

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00224 AC: 100 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00685 AC: 179 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86242

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53400

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5760

European-Non Finnish (NFE) AF: 0.000630 AC: 701 AN: 1111848

Other (OTH) AF: 0.00177 AC: 107 AN: 60372

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152240 Hom.: 0 Cov.: 31 AF XY: 0.00126 AC XY: 94 AN XY: 74420

African (AFR) AF: 0.000722 AC: 30 AN: 41550

American (AMR) AF: 0.00379 AC: 58 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68028

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

Alfa AF: 0.00125 Hom.: 2

Bravo AF: 0.00150

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00166

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		-0.97
Mutation Taster		=93/7	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: rs185794149; hg19: chr7-21913098;