chr15-43874310-C-T

Variant names:

• chr15-43874310-C-T
• rs754227679
• NM_032892.5:c.1288G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032892.5(FRMD5):​c.1288G>A​(p.Val430Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,226 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (1 hom.)
• Consequence: FRMD5 NM_032892.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• Publications: 0 publications found

Genes affected

FRMD5 (HGNC:28214): (FERM domain containing 5) Enables integrin binding activity and protein kinase binding activity. Involved in negative regulation of cell motility; positive regulation of cell adhesion; and regulation of cell migration. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

FRMD5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with eye movement abnormalities and ataxia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14186266).
• BS2: High AC in GnomAdExome4 at 51 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032892.5. 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
	FRMD5	NM_032892.5	MANE Select	c.1288G>A	p.Val430Met	missense	Exon 14 of 14	NP_116281.2	Q7Z6J6-1
	FRMD5	NM_001411124.1		c.1288G>A	p.Val430Met	missense	Exon 14 of 15	NP_001398053.1	B5MC67
	FRMD5	NM_001322949.2		c.1288G>A	p.Val430Met	missense	Exon 14 of 16	NP_001309878.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD5	ENST00000417257.6	TSL:1 MANE Select	c.1288G>A	p.Val430Met	missense	Exon 14 of 14	ENSP00000403067.1	Q7Z6J6-1
	FRMD5	ENST00000421674.5	TSL:1	n.*1232G>A		non_coding_transcript_exon	Exon 15 of 15	ENSP00000401635.1	F8WEJ8
	FRMD5	ENST00000458630.5	TSL:1	n.*1235G>A		non_coding_transcript_exon	Exon 15 of 15	ENSP00000404496.1	H7C282

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000678 AC: 17 AN: 250922 AF XY: 0.000111

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461868 Hom.: 1 Cov.: 32 AF XY: 0.0000468 AC XY: 34 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74504

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.22
Sift	Benign	0.18	T
Sift4G	Benign	0.25	T
Polyphen		0.081	B
Vest4		0.16
MutPred		0.27		Gain of helix (P = 0.062)
MVP		0.38
MPC		0.071
ClinPred		0.036	T
GERP RS		3.0
Varity_R		0.021
gMVP		0.52
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs754227679; hg19: chr15-44166508;