chr1-179044080-C-T

Position:

• chr1-179044080-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014864.4(FAM20B):​c.233C>T​(p.Pro78Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAM20B NM_014864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

FAM20B (HGNC:23017): (FAM20B glycosaminoglycan xylosylkinase) Enables phosphotransferase activity, alcohol group as acceptor. Predicted to be involved in proteoglycan biosynthetic process. Located in Golgi apparatus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM20B	NM_014864.4	c.233C>T	p.Pro78Leu	missense_variant	2/8	ENST00000263733.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM20B	ENST00000263733.5	c.233C>T	p.Pro78Leu	missense_variant	2/8	1	NM_014864.4	P1
FAM20B	ENST00000440702.5	c.233C>T	p.Pro78Leu	missense_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 11, 2023

The c.233C>T (p.P78L) alteration is located in exon 2 (coding exon 1) of the FAM20B gene. This alteration results from a C to T substitution at nucleotide position 233, causing the proline (P) at amino acid position 78 to be replaced by a leucine (L). 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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.11	T;D
Polyphen		1.0	.;D
Vest4		0.85
MutPred		0.41		Loss of disorder (P = 0.0272);Loss of disorder (P = 0.0272);
MVP		0.92
MPC		0.63
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.32
gMVP		0.88

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: rs1650660570; hg19: chr1-179013215;