9-83248282-C-T

Variant names:

• chr9-83248282-C-T
• rs182521075
• NM_174938.6:c.1430G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_174938.6(FRMD3):​c.1430G>A​(p.Arg477Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: FRMD3 NM_174938.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.763
• Publications: 1 publications found

Genes affected

FRMD3 (HGNC:24125): (FERM domain containing 3) The protein encoded by this gene is a single pass membrane protein primarily found in ovaries. A similar protein in erythrocytes helps determine the shape of red blood cells, but the function of the encoded protein has not been determined. There is some evidence that this is a tumor suppressor gene, and there is also evidence linking defects in this gene to susceptibility to diabetic nephropathy in type 1 diabetes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

FRMD3-AS1 (HGNC:55790): (FRMD3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028826058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD3	NM_174938.6	c.1430G>A	p.Arg477Lys	missense_variant	Exon 14 of 14	ENST00000304195.8	NP_777598.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD3	ENST00000304195.8	c.1430G>A	p.Arg477Lys	missense_variant	Exon 14 of 14	1	NM_174938.6	ENSP00000303508.3

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000682 AC: 17 AN: 249440 AF XY: 0.0000665

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.0000234 AC XY: 17 AN XY: 727244

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74470

African (AFR) AF: 0.000601 AC: 25 AN: 41564

American (AMR) AF: 0.000719 AC: 11 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000817 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.000509 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1430G>A (p.R477K) alteration is located in exon 1 (coding exon 1) of the FRMD3 gene. This alteration results from a G to A substitution at nucleotide position 1430, causing the arginine (R) at amino acid position 477 to be replaced by a lysine (K). 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	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.72
DEOGEN2	Benign	0.0024	.;.;.;T;.
Eigen	Benign	-0.066
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.060	.;.;N;N;.
PhyloP100		0.76
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.21	T;T;T;T;.
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		0.99	D;.;B;B;.
Vest4		0.10
MVP		0.60
MPC		0.18
ClinPred		0.023	T
GERP RS		4.8
Varity_R		0.095
gMVP		0.24
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs182521075; hg19: chr9-85863197;