3-69250082-C-G

Variant names:

• chr3-69250082-C-G
• rs4361282
• NM_015123.3:c.519G>C

Variant summary

Our verdict is Benign. The variant received -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. 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.

• 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
• Publications: 25 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FRMD4B	NM_015123.3	c.519G>C	p.Glu173Asp	missense_variant	Exon 6 of 23	ENST00000398540.8	NP_055938.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4B	ENST00000398540.8	c.519G>C	p.Glu173Asp	missense_variant	Exon 6 of 23	1	NM_015123.3	ENSP00000381549.3

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

GnomAD2 exomes AF: 0.226 AC: 56214 AN: 249008 AF XY: 0.221

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 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

African (AFR) AF: 0.323 AC: 10754 AN: 33264

American (AMR) AF: 0.234 AC: 10446 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5592 AN: 26064

East Asian (EAS) AF: 0.223 AC: 8827 AN: 39636

South Asian (SAS) AF: 0.163 AC: 14031 AN: 86086

European-Finnish (FIN) AF: 0.237 AC: 12649 AN: 53360

Middle Eastern (MID) AF: 0.189 AC: 1086 AN: 5750

European-Non Finnish (NFE) AF: 0.215 AC: 237162 AN: 1104738

Other (OTH) AF: 0.216 AC: 13012 AN: 60116

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

African (AFR) AF: 0.319 AC: 13247 AN: 41462

American (AMR) AF: 0.243 AC: 3715 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 747 AN: 3466

East Asian (EAS) AF: 0.261 AC: 1349 AN: 5178

South Asian (SAS) AF: 0.150 AC: 723 AN: 4820

European-Finnish (FIN) AF: 0.247 AC: 2609 AN: 10566

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15274 AN: 68000

Other (OTH) AF: 0.225 AC: 477 AN: 2116

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;.;.;.
PhyloP100		0.53
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
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs4361282; hg19: chr3-69299233; COSMIC: COSV68329076;