16-84176054-T-C

Position:

• chr16-84176054-T-C

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.1820T>C​(p.Phe607Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000605 in 1,614,072 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.16

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=0.006793767).
• BP6: Variant 16-84176054-T-C is Benign according to our data. Variant chr16-84176054-T-C is described in ClinVar as [Benign]. Clinvar id is 262947.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 = 0.00336 (512/152232) while in subpopulation AFR AF= 0.0119 (493/41524). AF 95% confidence interval is 0.011. There are 4 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1820T>C	p.Phe607Ser	missense_variant	11/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1820T>C	p.Phe607Ser	missense_variant	11/12	1	NM_178452.6	P1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 512 AN: 152114 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000855 AC: 215 AN: 251366 Hom.: 0 AF XY: 0.000574 AC XY: 78 AN XY: 135892

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000317 AC: 464 AN: 1461840 Hom.: 1 Cov.: 57 AF XY: 0.000275 AC XY: 200 AN XY: 727220

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152232 Hom.: 4 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74436

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.00367

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00107 AC: 130

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	Ambry Genetics	Sep 14, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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	Pathogenic	0.58
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.89	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.26	T;D
Polyphen		1.0	D;.
Vest4		0.69
MVP		0.76
MPC		0.19
ClinPred		0.051	T
GERP RS		4.9
Varity_R		0.52
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144628213; hg19: chr16-84209660;