7-21852546-C-T

Position:

• chr7-21852546-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):​c.10976C>T​(p.Ala3659Val) variant causes a missense change. The variant allele was found at a frequency of 0.000517 in 1,612,604 control chromosomes in the GnomAD database, including 13 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3659E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00088 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (10 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.17

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008890927).
• BP6: Variant 7-21852546-C-T is Benign according to our data. Variant chr7-21852546-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167000.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000881 (134/152172) while in subpopulation EAS AF= 0.023 (119/5174). AF 95% confidence interval is 0.0196. There are 3 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.10976C>T	p.Ala3659Val	missense_variant	67/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.10976C>T	p.Ala3659Val	missense_variant	67/82	5	NM_001277115.2	P1
DNAH11	ENST00000421290.1	n.159C>T		non_coding_transcript_exon_variant	2/4	4
DNAH11	ENST00000607413.5	n.239C>T		non_coding_transcript_exon_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152054 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00193 AC: 479 AN: 247872 Hom.: 6 AF XY: 0.00184 AC XY: 247 AN XY: 134452

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0260

Gnomad SAS exome AF: 0.0000994

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000479 AC: 699 AN: 1460432 Hom.: 10 Cov.: 33 AF XY: 0.000441 AC XY: 320 AN XY: 726446

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0137

Gnomad4 SAS exome AF: 0.000210

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.000881 AC: 134 AN: 152172 Hom.: 3 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74390

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0230

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000981 Hom.: 0

Bravo AF: 0.00107

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00191 AC: 231

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2020	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala3659Val in exon 67 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 3.0% (6/200) of Han Chinese chromo somes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.n ih.gov/projects/SNP; dbSNP rs150631721). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	.;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0089	T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	.;D;.
REVEL	Benign	0.20
Sift	Uncertain	0.0030	.;D;.
Vest4		0.42
MVP		0.55
ClinPred		0.092	T
GERP RS		5.3
Varity_R		0.41
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs150631721; hg19: chr7-21892164;