rs28549882

Positions:

• chr7-21744471-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001277115.2(DNAH11):​c.8188G>T​(p.Gly2730Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,613,728 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (19 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.337

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002471298).
• BP6: Variant 7-21744471-G-T is Benign according to our data. Variant chr7-21744471-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 238931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00692 (1053/152206) while in subpopulation AFR AF= 0.0245 (1017/41522). AF 95% confidence interval is 0.0232. There are 7 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.8188G>T	p.Gly2730Cys	missense_variant	50/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.8188G>T	p.Gly2730Cys	missense_variant	50/82	5	NM_001277115.2	P1
DNAH11	ENST00000605912.1	c.475-399G>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00692 AC: 1052 AN: 152088 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00178 AC: 442 AN: 248974 Hom.: 3 AF XY: 0.00154 AC XY: 208 AN XY: 135086

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.000928

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000776 AC: 1134 AN: 1461522 Hom.: 19 Cov.: 31 AF XY: 0.000677 AC XY: 492 AN XY: 727042

Gnomad4 AFR exome AF: 0.0296

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00692 AC: 1053 AN: 152206 Hom.: 7 Cov.: 33 AF XY: 0.00656 AC XY: 488 AN XY: 74414

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00134 Hom.: 2

Bravo AF: 0.00774

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0262 AC: 96

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00214 AC: 258

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 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. -
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

-

- -

Primary ciliary dyskinesia 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 16, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2023

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.3
DANN	Benign	0.87
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.30	T;T;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
Vest4		0.15
MVP		0.22
ClinPred		0.00042	T
GERP RS		0.81
Varity_R		0.11
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs28549882; hg19: chr7-21784089; COSMIC: COSV99078093;