rs143312655

Positions:

• chr16-84154656-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000378553.10(DNAAF1):​c.432C>T​(p.Ile144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,150 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: DNAAF1 ENST00000378553.10 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.458

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 16-84154656-C-T is Benign according to our data. Variant chr16-84154656-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.458 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000624 (95/152262) while in subpopulation AFR AF= 0.002 (83/41554). AF 95% confidence interval is 0.00165. There are 2 homozygotes in gnomad4. There are 46 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	Protein	UniProt
DNAAF1	NM_178452.6	c.432C>T	p.Ile144=	synonymous_variant	4/12	ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10	c.432C>T	p.Ile144=	synonymous_variant	4/12	1	NM_178452.6	ENSP00000367815	P1
DNAAF1	ENST00000567918.5	c.432C>T	p.Ile144=	synonymous_variant, NMD_transcript_variant	4/7	1		ENSP00000455154
DNAAF1	ENST00000570298.5	n.586C>T		non_coding_transcript_exon_variant	4/11	2
DNAAF1	ENST00000563093.5	c.432C>T	p.Ile144=	synonymous_variant, NMD_transcript_variant	4/11	2		ENSP00000457373

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251496 Hom.: 1 AF XY: 0.000140 AC XY: 19 AN XY: 135922

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000811 AC XY: 59 AN XY: 727246

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74432

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000377 Hom.: 0

Bravo AF: 0.000729

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2022	This alteration is classified as likely 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:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.0
DANN	Benign	0.62

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: rs143312655; hg19: chr16-84188261; COSMIC: COSV57577363; COSMIC: COSV57577363;