NM_015123.3:c.1186A>C

Variant names:

• chr3-69196303-T-G
• rs9310141
• NM_015123.3:c.1186A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015123.3(FRMD4B):​c.1186A>C​(p.Thr396Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,560 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. 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. T396M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FRMD4B NM_015123.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122146815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4B	NM_015123.3	c.1186A>C	p.Thr396Pro	missense_variant	Exon 14 of 23	ENST00000398540.8	NP_055938.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4B	ENST00000398540.8	c.1186A>C	p.Thr396Pro	missense_variant	Exon 14 of 23	1	NM_015123.3	ENSP00000381549.3
FRMD4B	ENST00000478263.5	c.142A>C	p.Thr48Pro	missense_variant	Exon 4 of 13	1		ENSP00000418682.1
FRMD4B	ENST00000462512.1	c.319A>C	p.Thr107Pro	missense_variant	Exon 4 of 5	4		ENSP00000419869.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457560 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725208

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 43876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00 AC: 0 AN: 85620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109748

Other (OTH) AF: 0.00 AC: 0 AN: 60176

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0036	T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.30	T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.34	N;.;.
PhyloP100		1.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.92	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.031	D;T;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0020	B;.;.
Vest4		0.085
MutPred		0.30		Loss of sheet (P = 0.0104);.;.;
MVP		0.51
MPC		0.060
ClinPred		0.29	T
GERP RS		6.1
Varity_R		0.24
gMVP		0.13
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9310141; hg19: chr3-69245454;