14-74047959-T-C

Variant names:

• chr14-74047959-T-C
• rs1391423538
• NM_025057.3:c.677T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025057.3(BBOF1):​c.677T>C​(p.Phe226Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BBOF1 NM_025057.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBOF1	NM_025057.3	c.677T>C	p.Phe226Ser	missense_variant	Exon 7 of 12	ENST00000394009.5	NP_079333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBOF1	ENST00000394009.5	c.677T>C	p.Phe226Ser	missense_variant	Exon 7 of 12	2	NM_025057.3	ENSP00000377577.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458210 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725118

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.677T>C (p.F226S) alteration is located in exon 7 (coding exon 7) of the BBOF1 gene. This alteration results from a T to C substitution at nucleotide position 677, causing the phenylalanine (F) at amino acid position 226 to be replaced by a serine (S). 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	2.9	.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	.;D
Vest4		0.85
MutPred		0.57		.;Gain of disorder (P = 0.0115);
MVP		0.66
MPC		0.56
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.52

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: rs1391423538; hg19: chr14-74514662;