rs4361282

chr3-69250082-C-Gchr3-69250082-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015123.3(FRMD4B):c.519G>C(p.Glu173Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,605,782 control chromosomes in the GnomAD database, including 39,727 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4977 hom., cov: 33)
  • Exomes 𝑓: 0.22 (34750 hom.)
• Consequence: FRMD4B NM_015123.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.526

Genes affected

FRMD4B (HGNC:24886): (FERM domain containing 4B) This gene encodes a GRP1-binding protein which contains a FERM protein interaction domain as well as two coiled coil domains. This protein may play a role as a scaffolding protein. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003638357).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD4B	NM_015123.3	c.519G>C	p.Glu173Asp	missense_variant	6/23	ENST00000398540.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD4B	ENST00000398540.8	c.519G>C	p.Glu173Asp	missense_variant	6/23	1	NM_015123.3	P1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38320 AN: 151976 Hom.: 4962 Cov.: 33

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.226 AC: 56214 AN: 249008 Hom.: 6505 AF XY: 0.221 AC XY: 29881 AN XY: 135078

Gnomad AFR exome AF: 0.325

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.271

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.216 AC: 313559 AN: 1453688 Hom.: 34750 Cov.: 29 AF XY: 0.214 AC XY: 154909 AN XY: 723726

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.252 AC: 38382 AN: 152094 Hom.: 4977 Cov.: 33 AF XY: 0.250 AC XY: 18586 AN XY: 74316

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.225

Alfa AF: 0.227 Hom.: 3151

Bravo AF: 0.256

TwinsUK AF: 0.220 AC: 816

ALSPAC AF: 0.217 AC: 837

ESP6500AA AF: 0.302 AC: 1174

ESP6500EA AF: 0.219 AC: 1816

ExAC AF: 0.226 AC: 27289

Asia WGS AF: 0.262 AC: 909 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	19
Dann	Benign	0.22
DEOGEN2	Benign	0.017	T;.;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.48	T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.26	N;.;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	1.3	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;.;.
Polyphen		0.0	B;.;.;.
Vest4		0.057
MutPred		0.40		Loss of disorder (P = 0.2093);.;.;.;
MPC		0.046
ClinPred		0.0058	T
GERP RS		4.3
Varity_R		0.070
gMVP		0.15

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: rs4361282; hg19: chr3-69299233; COSMIC: COSV68329076;