chr1-179066819-G-T

Position:

• chr1-179066819-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014864.4(FAM20B):​c.958G>T​(p.Asp320Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 9.75

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM20B	NM_014864.4	c.958G>T	p.Asp320Tyr	missense_variant	7/8	ENST00000263733.5	NP_055679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM20B	ENST00000263733.5	c.958G>T	p.Asp320Tyr	missense_variant	7/8	1	NM_014864.4	ENSP00000263733.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460684 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726754

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: 9.00e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.958G>T (p.D320Y) alteration is located in exon 7 (coding exon 6) of the FAM20B gene. This alteration results from a G to T substitution at nucleotide position 958, causing the aspartic acid (D) at amino acid position 320 to be replaced by a tyrosine (Y). 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	0.44
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.94		Loss of disorder (P = 0.0205);
MVP		0.91
MPC		0.75
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-179035954;