19-48601209-C-T

Variant names:

• chr19-48601209-C-T
• rs73579553
• NM_017708.4:c.1337G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017708.4(FAM83E):​c.1337G>A​(p.Arg446Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,611,484 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R446P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (47 hom.)
• Consequence: FAM83E NM_017708.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034745634).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017708.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83E	NM_017708.4	MANE Select	c.1337G>A	p.Arg446Gln	missense	Exon 7 of 7	NP_060178.2	Q2M2I3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83E	ENST00000263266.4	TSL:1 MANE Select	c.1337G>A	p.Arg446Gln	missense	Exon 7 of 7	ENSP00000263266.2	Q2M2I3
	FAM83E	ENST00000876133.1		c.1337G>A	p.Arg446Gln	missense	Exon 6 of 6	ENSP00000546192.1
	FAM83E	ENST00000876134.1		c.1337G>A	p.Arg446Gln	missense	Exon 6 of 6	ENSP00000546193.1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2323 AN: 152174 Hom.: 64 Cov.: 31

Gnomad AFR AF: 0.0528

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00425 AC: 1038 AN: 244218 AF XY: 0.00320

Gnomad AFR exome AF: 0.0586

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00288

GnomAD4 exome AF: 0.00173 AC: 2531 AN: 1459192 Hom.: 47 Cov.: 33 AF XY: 0.00150 AC XY: 1087 AN XY: 725692

African (AFR) AF: 0.0571 AC: 1907 AN: 33420

American (AMR) AF: 0.00410 AC: 182 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53104

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5754

European-Non Finnish (NFE) AF: 0.000161 AC: 179 AN: 1110588

Other (OTH) AF: 0.00390 AC: 235 AN: 60260

GnomAD4 genome AF: 0.0153 AC: 2333 AN: 152292 Hom.: 64 Cov.: 31 AF XY: 0.0145 AC XY: 1076 AN XY: 74456

African (AFR) AF: 0.0528 AC: 2196 AN: 41558

American (AMR) AF: 0.00640 AC: 98 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68026

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00581 Hom.: 35

Bravo AF: 0.0183

ESP6500AA AF: 0.0476 AC: 175

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.00480 AC: 580

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.57
DANN	Benign	0.81
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.26	N
PhyloP100		-1.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.0030
Sift	Benign	0.56	T
Sift4G	Benign	0.82	T
Polyphen		0.0010	B
Vest4		0.061
MVP		0.040
MPC		0.28
ClinPred		0.00069	T
GERP RS		-5.9
Varity_R		0.014
gMVP		0.062
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs73579553; hg19: chr19-49104466;