rs147912535

Positions:

• chr7-21570271-A-C

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.1397A>C​(p.Lys466Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 1,609,284 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (8 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.470

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]

LOC105375183 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004513085).
• BP6: Variant 7-21570271-A-C is Benign according to our data. Variant chr7-21570271-A-C is described in ClinVar as [Benign]. Clinvar id is 238900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21570271-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000565 (86/152320) while in subpopulation EAS AF= 0.0143 (74/5186). AF 95% confidence interval is 0.0117. There are 2 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.1397A>C	p.Lys466Thr	missense_variant	7/82	ENST00000409508.8
LOC105375183	XR_007060247.1	n.282+3055T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.1397A>C	p.Lys466Thr	missense_variant	7/82	5	NM_001277115.2	P1
DNAH11	ENST00000496218.1	n.283A>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000865 AC: 209 AN: 241638 Hom.: 1 AF XY: 0.000716 AC XY: 94 AN XY: 131376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.000723

Gnomad EAS exome AF: 0.00982

Gnomad SAS exome AF: 0.000415

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000531 AC: 774 AN: 1456964 Hom.: 8 Cov.: 30 AF XY: 0.000507 AC XY: 367 AN XY: 724440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000456

Gnomad4 ASJ exome AF: 0.000462

Gnomad4 EAS exome AF: 0.0158

Gnomad4 SAS exome AF: 0.000460

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000472 Hom.: 1

Bravo AF: 0.000514

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000986 AC: 119

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2016	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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.051	.;.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.37	T;T;T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;.;M
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	.;N;.
REVEL	Benign	0.10
Sift	Benign	0.40	.;T;.
Polyphen		0.10	.;.;B
Vest4		0.26
MVP		0.16
ClinPred		0.011	T
GERP RS		0.85
Varity_R		0.083
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147912535; hg19: chr7-21609889; COSMIC: COSV60983633;