rs902393

Positions:

• chr6-168062944-G-A

Variant summary

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

The NM_024919.6(FRMD1):​c.820C>T​(p.Arg274Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,611,900 control chromosomes in the GnomAD database, including 4,418 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.071 (389 hom., cov: 34)
  • Exomes 𝑓: 0.074 (4029 hom.)
• Consequence: FRMD1 NM_024919.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0720

Genes affected

FRMD1 (HGNC:21240): (FERM domain containing 1) Predicted to be involved in positive regulation of hippo signaling. Predicted to be located in cytoskeleton. Predicted to be active in cytoplasmic side of apical plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032986403).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD1	NM_024919.6	c.820C>T	p.Arg274Cys	missense_variant	7/11	ENST00000283309.11	NP_079195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD1	ENST00000283309.11	c.820C>T	p.Arg274Cys	missense_variant	7/11	1	NM_024919.6	ENSP00000283309

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10788 AN: 152098 Hom.: 390 Cov.: 34

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.0499

Gnomad SAS AF: 0.0771

Gnomad FIN AF: 0.0861

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0763

Gnomad OTH AF: 0.0612

GnomAD3 exomes AF: 0.0707 AC: 17780 AN: 251398 Hom.: 631 AF XY: 0.0717 AC XY: 9737 AN XY: 135870

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.0502

Gnomad ASJ exome AF: 0.0698

Gnomad EAS exome AF: 0.0550

Gnomad SAS exome AF: 0.0822

Gnomad FIN exome AF: 0.0852

Gnomad NFE exome AF: 0.0742

Gnomad OTH exome AF: 0.0645

GnomAD4 exome AF: 0.0739 AC: 107922 AN: 1459684 Hom.: 4029 Cov.: 32 AF XY: 0.0741 AC XY: 53817 AN XY: 726292

Gnomad4 AFR exome AF: 0.0651

Gnomad4 AMR exome AF: 0.0517

Gnomad4 ASJ exome AF: 0.0723

Gnomad4 EAS exome AF: 0.0518

Gnomad4 SAS exome AF: 0.0790

Gnomad4 FIN exome AF: 0.0887

Gnomad4 NFE exome AF: 0.0753

Gnomad4 OTH exome AF: 0.0692

GnomAD4 genome AF: 0.0710 AC: 10804 AN: 152216 Hom.: 389 Cov.: 34 AF XY: 0.0706 AC XY: 5252 AN XY: 74414

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.0530

Gnomad4 ASJ AF: 0.0657

Gnomad4 EAS AF: 0.0502

Gnomad4 SAS AF: 0.0775

Gnomad4 FIN AF: 0.0861

Gnomad4 NFE AF: 0.0763

Gnomad4 OTH AF: 0.0610

Alfa AF: 0.0725 Hom.: 1020

Bravo AF: 0.0684

TwinsUK AF: 0.0752 AC: 279

ALSPAC AF: 0.0760 AC: 293

ESP6500AA AF: 0.0670 AC: 295

ESP6500EA AF: 0.0719 AC: 618

ExAC AF: 0.0725 AC: 8807

Asia WGS AF: 0.0620 AC: 217 AN: 3478

EpiCase AF: 0.0682

EpiControl AF: 0.0680

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	3.5
DANN	Benign	0.79
DEOGEN2	Benign	0.030	.;.;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.66	T;T;T;T;T
MetaRNN	Benign	0.0033	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.84	.;.;L;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.9	.;.;D;D;.
REVEL	Benign	0.081
Sift	Benign	0.061	.;.;T;D;.
Sift4G	Benign	0.082	.;.;T;T;.
Polyphen		0.0040, 0.0060	.;.;B;B;.
Vest4		0.086, 0.13
MPC		0.14
ClinPred		0.0072	T
GERP RS		-1.9
Varity_R		0.10
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs902393; hg19: chr6-168463624; COSMIC: COSV51961481; COSMIC: COSV51961481;