19-48603693-G-A

Variant names:

• chr19-48603693-G-A
• rs887845430
• NM_017708.4:c.977C>T

Variant summary

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

The NM_017708.4(FAM83E):​c.977C>T​(p.Pro326Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,327,808 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: 𝑓 0.000060 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: FAM83E NM_017708.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.743

Genes affected

FAM83E (HGNC:25972): (family with sequence similarity 83 member E) Enables protein kinase binding activity. Predicted to be involved in signal transduction. [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=0.04698077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM83E	NM_017708.4	c.977C>T	p.Pro326Leu	missense_variant	Exon 6 of 7	ENST00000263266.4	NP_060178.2
FAM83E	XM_024451561.2	c.977C>T	p.Pro326Leu	missense_variant	Exon 6 of 7		XP_024307329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM83E	ENST00000263266.4	c.977C>T	p.Pro326Leu	missense_variant	Exon 6 of 7	1	NM_017708.4	ENSP00000263266.2

Frequencies

GnomAD3 genomes AF: 0.0000596 AC: 9 AN: 150978 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 25 AN: 1176830 Hom.: 0 Cov.: 30 AF XY: 0.0000210 AC XY: 12 AN XY: 571086

Gnomad4 AFR exome AF: 0.000306

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000387

Gnomad4 SAS exome AF: 0.0000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000134

Gnomad4 OTH exome AF: 0.0000642

GnomAD4 genome AF: 0.0000596 AC: 9 AN: 150978 Hom.: 0 Cov.: 30 AF XY: 0.0000678 AC XY: 5 AN XY: 73722

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.977C>T (p.P326L) alteration is located in exon 4 (coding exon 4) of the FAM83E gene. This alteration results from a C to T substitution at nucleotide position 977, causing the proline (P) at amino acid position 326 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	Benign	0.066
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.021
Sift	Benign	0.36	T
Sift4G	Benign	0.22	T
Polyphen		0.027	B
Vest4		0.25
MutPred		0.26		Loss of glycosylation at P326 (P = 0.0012);
MVP		0.072
MPC		0.24
ClinPred		0.070	T
GERP RS		2.5
Varity_R		0.026
gMVP		0.35

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: rs887845430; hg19: chr19-49106950; COSMIC: COSV52374621; COSMIC: COSV52374621;