rs28370951

chr7-21725876-G-Achr7-21725876-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001277115.2(DNAH11):c.7332G>A(p.Pro2444=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,609,796 control chromosomes in the GnomAD database, including 18 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 0.0060 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (11 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.49

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 7-21725876-G-A is Benign according to our data. Variant chr7-21725876-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257926.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00601 (915/152170) while in subpopulation AFR AF= 0.0213 (884/41496). AF 95% confidence interval is 0.0201. There are 7 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.7332G>A	p.Pro2444=	synonymous_variant	45/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.7332G>A	p.Pro2444=	synonymous_variant	45/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 913 AN: 152052 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00164 AC: 395 AN: 241428 Hom.: 3 AF XY: 0.00136 AC XY: 178 AN XY: 130506

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.000976

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000207

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.000696 AC: 1014 AN: 1457626 Hom.: 11 Cov.: 34 AF XY: 0.000605 AC XY: 438 AN XY: 724486

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.000926

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152170 Hom.: 7 Cov.: 33 AF XY: 0.00584 AC XY: 434 AN XY: 74370

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00122 Hom.: 2

Bravo AF: 0.00697

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 16, 2017	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	9.5
Dann	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs28370951; hg19: chr7-21765494;