6-168059165-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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. Q456R) has been classified as Uncertain significance.

• 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
• Publications: 19 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: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD1	NM_024919.6	MANE Select	c.1366C>G	p.Gln456Glu	missense	Exon 10 of 11	NP_079195.3
	FRMD1	NM_001394681.1		c.1171C>G	p.Gln391Glu	missense	Exon 9 of 10	NP_001381610.1
	FRMD1	NM_001122841.3		c.1162C>G	p.Gln388Glu	missense	Exon 10 of 11	NP_001116313.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD1	ENST00000283309.11	TSL:1 MANE Select	c.1366C>G	p.Gln456Glu	missense	Exon 10 of 11	ENSP00000283309.6
	FRMD1	ENST00000432403.5	TSL:1	n.1053C>G		non_coding_transcript_exon	Exon 8 of 9
	FRMD1	ENST00000646385.1		c.1561C>G	p.Gln521Glu	missense	Exon 13 of 14	ENSP00000494166.1

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

GnomAD2 exomes AF: 0.869 AC: 182724 AN: 210202 AF XY: 0.874

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 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

African (AFR) AF: 0.855 AC: 28431 AN: 33240

American (AMR) AF: 0.781 AC: 32672 AN: 41824

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 20834 AN: 25734

East Asian (EAS) AF: 0.840 AC: 32590 AN: 38812

South Asian (SAS) AF: 0.904 AC: 74662 AN: 82604

European-Finnish (FIN) AF: 0.898 AC: 40591 AN: 45212

Middle Eastern (MID) AF: 0.837 AC: 4404 AN: 5262

European-Non Finnish (NFE) AF: 0.909 AC: 1001268 AN: 1101992

Other (OTH) AF: 0.889 AC: 52883 AN: 59466

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

African (AFR) AF: 0.859 AC: 35680 AN: 41520

American (AMR) AF: 0.840 AC: 12845 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.816 AC: 2833 AN: 3472

East Asian (EAS) AF: 0.849 AC: 4366 AN: 5142

South Asian (SAS) AF: 0.903 AC: 4362 AN: 4828

European-Finnish (FIN) AF: 0.893 AC: 9470 AN: 10608

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61688 AN: 67968

Other (OTH) AF: 0.875 AC: 1847 AN: 2110

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 v4.9

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
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-1.1
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.039
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0060
MPC		0.11
ClinPred		0.000016	T
GERP RS		0.24
Varity_R		0.040
gMVP		0.057
Mutation Taster		=99/1	polymorphism (auto)

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: rs1548349; hg19: chr6-168459845; COSMIC: COSV107306477; COSMIC: COSV107306477;