14-74019528-A-T

Position:

• chr14-74019528-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025057.3(BBOF1):​c.50A>T​(p.Asp17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BBOF1 NM_025057.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

Genes affected

BBOF1 (HGNC:19855): (basal body orientation factor 1) Predicted to be involved in motile cilium assembly. Predicted to be located in ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045140833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBOF1	NM_025057.3	c.50A>T	p.Asp17Val	missense_variant	1/12	ENST00000394009.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBOF1	ENST00000394009.5	c.50A>T	p.Asp17Val	missense_variant	1/12	2	NM_025057.3	P1
BBOF1	ENST00000463558.3	c.-142A>T		5_prime_UTR_variant	1/4	2
BBOF1	ENST00000464394.5	c.-142A>T		5_prime_UTR_variant	1/6	3
BBOF1	ENST00000489323.5	n.83A>T		non_coding_transcript_exon_variant	1/6	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446830 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718586

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

The c.50A>T (p.D17V) alteration is located in exon 1 (coding exon 1) of the BBOF1 gene. This alteration results from a A to T substitution at nucleotide position 50, causing the aspartic acid (D) at amino acid position 17 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.040
Sift	Uncertain	0.010	D
Sift4G	Benign	0.29	T
Polyphen		0.0020	B
Vest4		0.28
MutPred		0.17		Loss of solvent accessibility (P = 0.0169);
MVP		0.11
MPC		0.10
ClinPred		0.049	T
GERP RS		-0.18
Varity_R		0.17
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs759708180; hg19: chr14-74486231;