6-168059165-G-C

Variant names:

• chr6-168059165-G-C
• rs1548349
• NM_024919.6:c.1366C>G

Variant summary

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

The NM_024919.6(FRMD1):​c.1366C>G​(p.Gln456Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.897 in 1,586,290 control chromosomes in the GnomAD database, including 638,635 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.88 (59273 hom., cov: 32)
  • Exomes 𝑓: 0.90 (579362 hom.)
• Consequence: FRMD1 NM_024919.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09

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=8.692425E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD1	NM_024919.6	c.1366C>G	p.Gln456Glu	missense_variant	Exon 10 of 11	ENST00000283309.11	NP_079195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD1	ENST00000283309.11	c.1366C>G	p.Gln456Glu	missense_variant	Exon 10 of 11	1	NM_024919.6	ENSP00000283309.6

Frequencies

GnomAD3 genomes AF: 0.882 AC: 134153 AN: 152028 Hom.: 59230 Cov.: 32

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.849

Gnomad SAS AF: 0.903

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.876

GnomAD3 exomes AF: 0.869 AC: 182724 AN: 210202 Hom.: 79735 AF XY: 0.874 AC XY: 99466 AN XY: 113768

Gnomad AFR exome AF: 0.850

Gnomad AMR exome AF: 0.773

Gnomad ASJ exome AF: 0.803

Gnomad EAS exome AF: 0.848

Gnomad SAS exome AF: 0.905

Gnomad FIN exome AF: 0.894

Gnomad NFE exome AF: 0.901

Gnomad OTH exome AF: 0.857

GnomAD4 exome AF: 0.898 AC: 1288335 AN: 1434146 Hom.: 579362 Cov.: 51 AF XY: 0.898 AC XY: 639055 AN XY: 711476

Gnomad4 AFR exome AF: 0.855

Gnomad4 AMR exome AF: 0.781

Gnomad4 ASJ exome AF: 0.810

Gnomad4 EAS exome AF: 0.840

Gnomad4 SAS exome AF: 0.904

Gnomad4 FIN exome AF: 0.898

Gnomad4 NFE exome AF: 0.909

Gnomad4 OTH exome AF: 0.889

GnomAD4 genome AF: 0.882 AC: 134251 AN: 152144 Hom.: 59273 Cov.: 32 AF XY: 0.883 AC XY: 65661 AN XY: 74374

Gnomad4 AFR AF: 0.859

Gnomad4 AMR AF: 0.840

Gnomad4 ASJ AF: 0.816

Gnomad4 EAS AF: 0.849

Gnomad4 SAS AF: 0.903

Gnomad4 FIN AF: 0.893

Gnomad4 NFE AF: 0.908

Gnomad4 OTH AF: 0.875

Alfa AF: 0.873 Hom.: 6234

Bravo AF: 0.874

TwinsUK AF: 0.904 AC: 3351

ALSPAC AF: 0.913 AC: 3518

ESP6500AA AF: 0.865 AC: 3786

ESP6500EA AF: 0.899 AC: 7717

ExAC AF: 0.864 AC: 102343

Asia WGS AF: 0.883 AC: 3071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0020
DANN	Benign	0.36
DEOGEN2	Benign	0.0010	.;.;T;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.16	T;T;T;T;T
MetaRNN	Benign	8.7e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	.;.;N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.080	.;.;N;N;.
REVEL	Benign	0.039
Sift	Benign	1.0	.;.;T;T;.
Sift4G	Benign	1.0	.;.;T;T;.
Polyphen		0.0	.;.;B;B;.
Vest4		0.0060, 0.015
MPC		0.11
ClinPred		0.000016	T
GERP RS		0.24
Varity_R		0.040
gMVP		0.057

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

Publications

LitVar

Other links and lift over

dbSNP: rs1548349; hg19: chr6-168459845;