3-69196303-T-C

Position:

• chr3-69196303-T-C

Variant summary

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

The NM_015123.3(FRMD4B):​c.1186A>G​(p.Thr396Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,609,808 control chromosomes in the GnomAD database, including 796,336 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.97 (71863 hom., cov: 32)
  • Exomes 𝑓: 1.0 (724473 hom.)
• Consequence: FRMD4B NM_015123.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72

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=5.564749E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD4B	NM_015123.3	c.1186A>G	p.Thr396Ala	missense_variant	14/23	ENST00000398540.8	NP_055938.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD4B	ENST00000398540.8	c.1186A>G	p.Thr396Ala	missense_variant	14/23	1	NM_015123.3	ENSP00000381549.3
FRMD4B	ENST00000478263.5	c.142A>G	p.Thr48Ala	missense_variant	4/13	1		ENSP00000418682.1
FRMD4B	ENST00000462512.1	c.319A>G	p.Thr107Ala	missense_variant	4/5	4		ENSP00000419869.1

Frequencies

GnomAD3 genomes AF: 0.971 AC: 147693 AN: 152174 Hom.: 71823 Cov.: 32

Gnomad AFR AF: 0.897

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.990

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.977

GnomAD3 exomes AF: 0.993 AC: 244484 AN: 246234 Hom.: 121457 AF XY: 0.994 AC XY: 132988 AN XY: 133724

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.997 AC: 1453016 AN: 1457516 Hom.: 724473 Cov.: 32 AF XY: 0.997 AC XY: 723218 AN XY: 725192

Gnomad4 AFR exome AF: 0.892

Gnomad4 AMR exome AF: 0.995

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.993

GnomAD4 genome AF: 0.970 AC: 147789 AN: 152292 Hom.: 71863 Cov.: 32 AF XY: 0.971 AC XY: 72270 AN XY: 74462

Gnomad4 AFR AF: 0.897

Gnomad4 AMR AF: 0.990

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.977

Alfa AF: 0.994 Hom.: 118023

Bravo AF: 0.966

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.899 AC: 3469

ESP6500EA AF: 1.00 AC: 8236

ExAC AF: 0.991 AC: 119766

Asia WGS AF: 0.993 AC: 3455 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.0016	T;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.032	T;T;T
MetaRNN	Benign	5.6e-7	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.3	N;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.32	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.012
MPC		0.048
ClinPred		0.010	T
GERP RS		6.1
Varity_R		0.040
gMVP		0.086

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

Publications

LitVar

Other links and lift over

dbSNP: rs9310141; hg19: chr3-69245454;