NM_001277115.2:c.2454A>G

Variant names:

• chr7-21591364-A-G
• rs4615458
• NM_001277115.2:c.2454A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001277115.2(DNAH11):​c.2454A>G​(p.Ala818Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,613,416 control chromosomes in the GnomAD database, including 148,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A818A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.45 (16236 hom., cov: 31)
  • Exomes 𝑓: 0.42 (131804 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.914
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-21591364-A-G is Benign according to our data. Variant chr7-21591364-A-G is described in ClinVar as Benign. ClinVar VariationId is 93684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.914 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

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.2454A>G	p.Ala818Ala	synonymous	Exon 14 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.2454A>G	p.Ala818Ala	synonymous	Exon 14 of 82	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68478 AN: 151740 Hom.: 16205 Cov.: 31

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.428 AC: 106424 AN: 248642 AF XY: 0.428

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.782

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.419 AC: 611928 AN: 1461558 Hom.: 131804 Cov.: 59 AF XY: 0.417 AC XY: 303393 AN XY: 727058

African (AFR) AF: 0.547 AC: 18303 AN: 33470

American (AMR) AF: 0.336 AC: 15024 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9228 AN: 26128

East Asian (EAS) AF: 0.753 AC: 29900 AN: 39700

South Asian (SAS) AF: 0.424 AC: 36545 AN: 86240

European-Finnish (FIN) AF: 0.396 AC: 21142 AN: 53386

Middle Eastern (MID) AF: 0.394 AC: 2270 AN: 5766

European-Non Finnish (NFE) AF: 0.408 AC: 453284 AN: 1111774

Other (OTH) AF: 0.434 AC: 26232 AN: 60374

GnomAD4 genome AF: 0.451 AC: 68551 AN: 151858 Hom.: 16236 Cov.: 31 AF XY: 0.451 AC XY: 33499 AN XY: 74226

African (AFR) AF: 0.552 AC: 22854 AN: 41392

American (AMR) AF: 0.385 AC: 5882 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1189 AN: 3472

East Asian (EAS) AF: 0.780 AC: 3993 AN: 5118

South Asian (SAS) AF: 0.442 AC: 2113 AN: 4778

European-Finnish (FIN) AF: 0.392 AC: 4149 AN: 10576

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27192 AN: 67942

Other (OTH) AF: 0.440 AC: 924 AN: 2102

Alfa AF: 0.422 Hom.: 7696

Bravo AF: 0.456

Asia WGS AF: 0.605 AC: 2104 AN: 3478

EpiCase AF: 0.396

EpiControl AF: 0.398

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.53
DANN	Benign	0.40
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

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: rs4615458; hg19: chr7-21630982; COSMIC: COSV60940541;