rs72655969

Positions:

• chr7-21545075-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001277115.2(DNAH11):​c.421G>T​(p.Asp141Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,606,810 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (98 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (104 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.69

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=0.0028721988).
• BP6: Variant 7-21545075-G-T is Benign according to our data. Variant chr7-21545075-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 257892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21545075-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.421G>T	p.Asp141Tyr	missense_variant	2/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.421G>T	p.Asp141Tyr	missense_variant	2/82	5	NM_001277115.2	ENSP00000475939	P1
DNAH11	ENST00000607050.1	n.411G>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3079 AN: 152014 Hom.: 99 Cov.: 31

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00603 AC: 1438 AN: 238402 Hom.: 46 AF XY: 0.00490 AC XY: 632 AN XY: 128924

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.00366

Gnomad ASJ exome AF: 0.00112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000653

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00262 AC: 3813 AN: 1454678 Hom.: 104 Cov.: 30 AF XY: 0.00244 AC XY: 1763 AN XY: 722836

Gnomad4 AFR exome AF: 0.0744

Gnomad4 AMR exome AF: 0.00403

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00463

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000313

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.0203 AC: 3084 AN: 152132 Hom.: 98 Cov.: 31 AF XY: 0.0198 AC XY: 1471 AN XY: 74368

Gnomad4 AFR AF: 0.0695

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00582

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00397 Hom.: 31

Bravo AF: 0.0233

ESP6500AA AF: 0.0701 AC: 256

ESP6500EA AF: 0.000734 AC: 6

ExAC AF: 0.00731 AC: 883

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Uncertain	0.42	.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;.;M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.1	.;D;.
REVEL	Benign	0.12
Sift	Uncertain	0.0020	.;D;.
Polyphen		0.95	.;.;P
Vest4		0.36
MVP		0.33
ClinPred		0.033	T
GERP RS		3.3
Varity_R		0.069
gMVP		0.34

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: rs72655969; hg19: chr7-21584693;