6-168061821-C-G

Position:

• chr6-168061821-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024919.6(FRMD1):​c.1031G>C​(p.Arg344Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000064 in 1,405,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: FRMD1 NM_024919.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD1	NM_024919.6	c.1031G>C	p.Arg344Pro	missense_variant	8/11	ENST00000283309.11	NP_079195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD1	ENST00000283309.11	c.1031G>C	p.Arg344Pro	missense_variant	8/11	1	NM_024919.6	ENSP00000283309

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000610 AC: 1 AN: 163980 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 87900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000154

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000640 AC: 9 AN: 1405204 Hom.: 0 Cov.: 31 AF XY: 0.00000432 AC XY: 3 AN XY: 694128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000738

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1031G>C (p.R344P) alteration is located in exon 8 (coding exon 8) of the FRMD1 gene. This alteration results from a G to C substitution at nucleotide position 1031, causing the arginine (R) at amino acid position 344 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	.;.;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	.;.;L;.;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	.;.;N;N;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0060	.;.;D;D;.
Sift4G	Uncertain	0.028	.;.;D;D;.
Polyphen		0.99, 0.99	.;.;D;D;.
Vest4		0.31, 0.30
MVP		0.79
MPC		0.41
ClinPred		0.83	D
GERP RS		-0.42
Varity_R		0.45
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs536431360; hg19: chr6-168462501;