chr6-168057264-C-A

Position:

• chr6-168057264-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024919.6(FRMD1):​c.1483G>T​(p.Ala495Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FRMD1 NM_024919.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.500

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09934902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD1	NM_024919.6	c.1483G>T	p.Ala495Ser	missense_variant	11/11	ENST00000283309.11	NP_079195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD1	ENST00000283309.11	c.1483G>T	p.Ala495Ser	missense_variant	11/11	1	NM_024919.6	ENSP00000283309

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459158 Hom.: 0 Cov.: 59 AF XY: 0.00000138 AC XY: 1 AN XY: 725822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

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

Dec 27, 2023

The c.1483G>T (p.A495S) alteration is located in exon 11 (coding exon 11) of the FRMD1 gene. This alteration results from a G to T substitution at nucleotide position 1483, causing the alanine (A) at amino acid position 495 to be replaced by a serine (S). 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	Benign	0.085
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.7
DANN	Benign	0.92
DEOGEN2	Benign	0.0031	.;.;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.51	T;T;T;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.099	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;.;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.58	.;.;N;N;.
REVEL	Benign	0.037
Sift	Uncertain	0.018	.;.;D;D;.
Sift4G	Benign	0.22	.;.;T;T;.
Polyphen		0.86, 0.73	.;.;P;P;.
Vest4		0.026, 0.017
MutPred		0.25		.;.;Gain of relative solvent accessibility (P = 0.0215);.;.;
MVP		0.35
MPC		0.19
ClinPred		0.13	T
GERP RS		-0.98
Varity_R		0.079
gMVP		0.058

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-168457944;