11-95789430-G-A

Variant names:

• chr11-95789430-G-A
• rs762964185
• NM_144664.5:c.49C>T

Variant summary

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

The NM_144664.5(FAM76B):​c.49C>T​(p.Pro17Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,457,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FAM76B NM_144664.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

Genes affected

FAM76B (HGNC:28492): (family with sequence similarity 76 member B) Located in nuclear speck. [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
FAM76B	NM_144664.5	c.49C>T	p.Pro17Ser	missense_variant	Exon 1 of 10	ENST00000358780.10	NP_653265.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM76B	ENST00000358780.10	c.49C>T	p.Pro17Ser	missense_variant	Exon 1 of 10	1	NM_144664.5	ENSP00000351631.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000843 AC: 2 AN: 237248 Hom.: 0 AF XY: 0.00000772 AC XY: 1 AN XY: 129520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457414 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 724660

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: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49C>T (p.P17S) alteration is located in exon 1 (coding exon 1) of the FAM76B gene. This alteration results from a C to T substitution at nucleotide position 49, causing the proline (P) at amino acid position 17 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	0.86
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.35		Loss of glycosylation at P17 (P = 0.0583);Loss of glycosylation at P17 (P = 0.0583);
MVP		0.77
MPC		0.68
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.78
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762964185; hg19: chr11-95522594;