rs115367126

chr7-21658973-C-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.5270C>T(p.Ala1757Val) variant causes a missense change. The variant allele was found at a frequency of 0.00072 in 1,610,226 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1757S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (6 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.42

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=0.008724391).
• BP6: Variant 7-21658973-C-T is Benign according to our data. Variant chr7-21658973-C-T is described in ClinVar as [Benign]. Clinvar id is 257903.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 = 0.00376 (571/152016) while in subpopulation AFR AF= 0.0131 (545/41460). AF 95% confidence interval is 0.0122. There are 4 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.5270C>T	p.Ala1757Val	missense_variant	30/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.5270C>T	p.Ala1757Val	missense_variant	30/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 569 AN: 151900 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

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: 0.00

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000933 AC: 227 AN: 243350 Hom.: 2 AF XY: 0.000683 AC XY: 90 AN XY: 131754

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000709

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000841

GnomAD4 exome AF: 0.000404 AC: 589 AN: 1458210 Hom.: 6 Cov.: 31 AF XY: 0.000366 AC XY: 265 AN XY: 724930

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.000904

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000797

GnomAD4 genome AF: 0.00376 AC: 571 AN: 152016 Hom.: 4 Cov.: 31 AF XY: 0.00365 AC XY: 271 AN XY: 74316

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00153 Hom.: 1

Bravo AF: 0.00436

ESP6500AA AF: 0.0140 AC: 52

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00115 AC: 139

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2015	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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
Vest4		0.37
MVP		0.47
ClinPred		0.021	T
GERP RS		6.0
Varity_R		0.16
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: rs115367126; hg19: chr7-21698591;