rs16931555

Variant names:

• chr9-34500798-A-C
• rs16931555
• NM_012144.4:c.978A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012144.4(DNAI1):​c.978A>C​(p.Gln326His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,112 control chromosomes in the GnomAD database, including 56 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q326Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0097 (32 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (24 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.90
• Publications: 2 publications found

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]

DNAI1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00628832).
• BP6: Variant 9-34500798-A-C is Benign according to our data. Variant chr9-34500798-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240859.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 = 0.00971 (1478/152246) while in subpopulation AFR AF = 0.0328 (1362/41534). AF 95% confidence interval is 0.0313. There are 32 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012144.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	NM_012144.4	MANE Select	c.978A>C	p.Gln326His	missense	Exon 11 of 20	NP_036276.1
	DNAI1	NM_001281428.2		c.990A>C	p.Gln330His	missense	Exon 11 of 20	NP_001268357.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	ENST00000242317.9	TSL:1 MANE Select	c.978A>C	p.Gln326His	missense	Exon 11 of 20	ENSP00000242317.4
	DNAI1	ENST00000614641.4	TSL:5	c.990A>C	p.Gln330His	missense	Exon 11 of 20	ENSP00000480538.1

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1471 AN: 152128 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00248 AC: 623 AN: 251382 AF XY: 0.00180

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000992 AC: 1450 AN: 1461866 Hom.: 24 Cov.: 31 AF XY: 0.000875 AC XY: 636 AN XY: 727228

African (AFR) AF: 0.0342 AC: 1146 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111992

Other (OTH) AF: 0.00252 AC: 152 AN: 60396

GnomAD4 genome AF: 0.00971 AC: 1478 AN: 152246 Hom.: 32 Cov.: 32 AF XY: 0.00948 AC XY: 706 AN XY: 74442

African (AFR) AF: 0.0328 AC: 1362 AN: 41534

American (AMR) AF: 0.00614 AC: 94 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00315 Hom.: 17

Bravo AF: 0.0112

ESP6500AA AF: 0.0340 AC: 150

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Primary ciliary dyskinesia (3)
-	-	2	Kartagener syndrome (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.30
Sift	Benign	0.56	T
Sift4G	Benign	0.58	T
Polyphen		0.0050	B
Vest4		0.54
MutPred		0.12		Loss of sheet (P = 0.0817)
MVP		0.83
MPC		0.11
ClinPred		0.0038	T
GERP RS		1.4
Varity_R		0.16
gMVP		0.65
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs16931555; hg19: chr9-34500796;