chr3-69196303-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 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
• Publications: 28 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=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 rank	MANE	Protein	UniProt
FRMD4B	NM_015123.3	c.1186A>G	p.Thr396Ala	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>G	p.Thr396Ala	missense_variant	Exon 14 of 23	1	NM_015123.3	ENSP00000381549.3
FRMD4B	ENST00000478263.5	c.142A>G	p.Thr48Ala	missense_variant	Exon 4 of 13	1		ENSP00000418682.1
FRMD4B	ENST00000462512.1	c.319A>G	p.Thr107Ala	missense_variant	Exon 4 of 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

GnomAD2 exomes AF: 0.993 AC: 244484 AN: 246234 AF XY: 0.994

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 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

African (AFR) AF: 0.892 AC: 29724 AN: 33316

American (AMR) AF: 0.995 AC: 43647 AN: 43872

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26110 AN: 26110

East Asian (EAS) AF: 1.00 AC: 39522 AN: 39522

South Asian (SAS) AF: 1.00 AC: 85587 AN: 85620

European-Finnish (FIN) AF: 1.00 AC: 53394 AN: 53394

Middle Eastern (MID) AF: 0.995 AC: 5737 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1109558 AN: 1109748

Other (OTH) AF: 0.993 AC: 59737 AN: 60170

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

African (AFR) AF: 0.897 AC: 37259 AN: 41542

American (AMR) AF: 0.990 AC: 15136 AN: 15282

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5182

South Asian (SAS) AF: 1.00 AC: 4824 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68022 AN: 68044

Other (OTH) AF: 0.977 AC: 2065 AN: 2114

Alfa AF: 0.988 Hom.: 144851

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;.;.
PhyloP100		1.7
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
Mutation Taster		=92/8	polymorphism (auto)

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; COSMIC: COSV107508427; COSMIC: COSV107508427;