rs141157671

chr9-34490387-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_012144.4(DNAI1):c.520G>A(p.Glu174Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E174E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.15

Genes affected

DNAI1 (HGNC:2954): (dynein axonemal intermediate chain 1) This gene encodes a member of the dynein intermediate chain family. The encoded protein is part of the dynein complex in respiratory cilia. The inner- and outer-arm dyneins, which bridge between the doublet microtubules in axonemes, are the force-generating proteins responsible for the sliding movement in axonemes. The intermediate and light chains, thought to form the base of the dynein arm, help mediate attachment and may also participate in regulating dynein activity. Mutations in this gene result in abnormal ciliary ultrastructure and function associated with primary ciliary dyskinesia and Kartagener syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02376008).
• BP6: Variant 9-34490387-G-A is Benign according to our data. Variant chr9-34490387-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551835.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4	c.520G>A	p.Glu174Lys	missense_variant	7/20	ENST00000242317.9
DNAI1	NM_001281428.2	c.532G>A	p.Glu178Lys	missense_variant	7/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.520G>A	p.Glu174Lys	missense_variant	7/20	1	NM_012144.4
DNAI1	ENST00000614641.4	c.532G>A	p.Glu178Lys	missense_variant	7/20	5		P1
DNAI1	ENST00000437363.5	c.487G>A	p.Glu163Lys	missense_variant	6/9	5
DNAI1	ENST00000488369.1	n.636G>A		non_coding_transcript_exon_variant	7/9	3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251490 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461088 Hom.: 0 Cov.: 32 AF XY: 0.000106 AC XY: 77 AN XY: 726682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in the published literature (Failly et al., 2008; Kim et al., 2014) in individuals with primary ciliary dyskinesia, with no second DNAI1 variant identified; This variant is associated with the following publications: (PMID: 18434704, 24498942) -

Kartagener syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 09, 2017

- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.027	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.024	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.61	N
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0030	.;.;B
Vest4		0.74
MVP		0.77
MPC		0.13
ClinPred		0.064	T
GERP RS		4.2
Varity_R		0.082
gMVP		0.50

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: rs141157671; hg19: chr9-34490385; COSMIC: COSV54279523; COSMIC: COSV54279523;