6-168060775-C-A

Variant names:

• chr6-168060775-C-A
• rs145114715
• NM_024919.6:c.1328G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024919.6(FRMD1):​c.1328G>T​(p.Arg443Leu) 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 1,457,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. R443H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FRMD1 NM_024919.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.481
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05825591).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024919.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD1	NM_024919.6	MANE Select	c.1328G>T	p.Arg443Leu	missense	Exon 9 of 11	NP_079195.3
	FRMD1	NM_001394681.1		c.1133G>T	p.Arg378Leu	missense	Exon 8 of 10	NP_001381610.1	A0A2R8Y6M2
	FRMD1	NM_001122841.3		c.1124G>T	p.Arg375Leu	missense	Exon 9 of 11	NP_001116313.1	Q8N878-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD1	ENST00000283309.11	TSL:1 MANE Select	c.1328G>T	p.Arg443Leu	missense	Exon 9 of 11	ENSP00000283309.6	Q8N878-1
	FRMD1	ENST00000432403.5	TSL:1	n.1015G>T		non_coding_transcript_exon	Exon 7 of 9
	FRMD1	ENST00000646385.1		c.1523G>T	p.Arg508Leu	missense	Exon 12 of 14	ENSP00000494166.1	A0A2R8Y4L9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457258 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724076

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108820

Other (OTH) AF: 0.00 AC: 0 AN: 60186

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.15
DANN	Benign	0.72
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.48
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.029
Sift	Benign	0.39	T
Sift4G	Benign	0.52	T
Polyphen		0.042	B
Vest4		0.13
MutPred		0.40		Loss of solvent accessibility (P = 1e-04)
MVP		0.18
MPC		0.13
ClinPred		0.10	T
GERP RS		-4.7
Varity_R		0.039
gMVP		0.11
Mutation Taster		=98/2	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: rs145114715; hg19: chr6-168461455;