rs551990619

Positions:

• chr16-84145552-G-A
• chr16-84145552-G-C
• chr16-84145552-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_178452.6(DNAAF1):​c.112G>A​(p.Gly38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,548,882 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (39 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025403202).
• BP6: Variant 16-84145552-G-A is Benign according to our data. Variant chr16-84145552-G-A is described in ClinVar as [Benign]. Clinvar id is 215544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000643 (98/152320) while in subpopulation SAS AF= 0.0199 (96/4834). AF 95% confidence interval is 0.0166. There are 2 homozygotes in gnomad4. There are 73 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.112G>A	p.Gly38Ser	missense_variant	1/12	ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10	c.112G>A	p.Gly38Ser	missense_variant	1/12	1	NM_178452.6	ENSP00000367815	P1
DNAAF1	ENST00000567918.5	c.112G>A	p.Gly38Ser	missense_variant, NMD_transcript_variant	1/7	1		ENSP00000455154
DNAAF1	ENST00000570298.5	n.266G>A		non_coding_transcript_exon_variant	1/11	2
DNAAF1	ENST00000563093.5	c.112G>A	p.Gly38Ser	missense_variant, NMD_transcript_variant	1/11	2		ENSP00000457373

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0198

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00296 AC: 446 AN: 150732 Hom.: 11 AF XY: 0.00416 AC XY: 333 AN XY: 79996

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000812

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0192

Gnomad FIN exome AF: 0.0000740

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.000922

GnomAD4 exome AF: 0.00120 AC: 1679 AN: 1396562 Hom.: 39 Cov.: 31 AF XY: 0.00177 AC XY: 1221 AN XY: 688968

Gnomad4 AFR exome AF: 0.0000630

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0200

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74468

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00232 AC: 206

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2017	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.0
DANN	Benign	0.72
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.013
Sift	Benign	0.50	T
Sift4G	Benign	0.83	T
Polyphen		0.0060	B
Vest4		0.077
MutPred		0.074		Gain of phosphorylation at G38 (P = 0.0077);
MVP		0.040
MPC		0.020
ClinPred		0.0052	T
GERP RS		-0.93
Varity_R		0.030
gMVP		0.17

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: rs551990619; hg19: chr16-84179157;