NM_012144.4:c.-170T>A

Variant names:

• chr9-34458836-T-A
• rs55750068
• NM_012144.4:c.-170T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_012144.4(DNAI1):​c.-170T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 697,552 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: DNAI1 NM_012144.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.364
• 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]

FAM219A (HGNC:19920): (family with sequence similarity 219 member A) The protein encoded by this gene has homologs that have been identified in mouse, macaque, etc organisms. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00265 (404/152250) while in subpopulation NFE AF = 0.0044 (299/68004). AF 95% confidence interval is 0.00399. There are 1 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	NM_012144.4	MANE Select	c.-170T>A		5_prime_UTR	Exon 1 of 20	NP_036276.1	A0A140VJI0
	DNAI1	NM_001281428.2		c.-170T>A		5_prime_UTR	Exon 1 of 20	NP_001268357.1	A0A087WWV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	ENST00000242317.9	TSL:1 MANE Select	c.-170T>A		5_prime_UTR	Exon 1 of 20	ENSP00000242317.4	Q9UI46-1
	DNAI1	ENST00000878474.1		c.-170T>A		5_prime_UTR	Exon 1 of 21	ENSP00000548533.1
	DNAI1	ENST00000614641.4	TSL:5	c.-170T>A		5_prime_UTR	Exon 1 of 20	ENSP00000480538.1	A0A087WWV9

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 404 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

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: 0.00441

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00288 AC: 1573 AN: 545302 Hom.: 4 Cov.: 6 AF XY: 0.00279 AC XY: 816 AN XY: 292888

African (AFR) AF: 0.000715 AC: 11 AN: 15394

American (AMR) AF: 0.00492 AC: 165 AN: 33508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18510

East Asian (EAS) AF: 0.00 AC: 0 AN: 31710

South Asian (SAS) AF: 0.0000167 AC: 1 AN: 60000

European-Finnish (FIN) AF: 0.000318 AC: 13 AN: 40932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3258

European-Non Finnish (NFE) AF: 0.00409 AC: 1278 AN: 312254

Other (OTH) AF: 0.00353 AC: 105 AN: 29736

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74442

African (AFR) AF: 0.000746 AC: 31 AN: 41560

American (AMR) AF: 0.00431 AC: 66 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00440 AC: 299 AN: 68004

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00106 Hom.: 1

Bravo AF: 0.00325

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.2
DANN	Benign	0.67
PhyloP100		-0.36
PromoterAI		0.087	Neutral
Mutation Taster		=298/2	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: rs55750068; hg19: chr9-34458834;