13-98435676-T-G

Variant names:

• chr13-98435676-T-G
• rs140045465
• NM_005766.4:c.2244T>G

Variant summary

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

The NM_005766.4(FARP1):​c.2244T>G​(p.Ile748Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,614,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: FARP1 NM_005766.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.482

Genes affected

FARP1 (HGNC:3591): (FERM, ARH/RhoGEF and pleckstrin domain protein 1) This gene encodes a protein containing a FERM (4.2, exrin, radixin, moesin) domain, a Dbl homology domain, and two pleckstrin homology domains. These domains are found in guanine nucleotide exchange factors and proteins that link the cytoskeleton to the cell membrane. The encoded protein functions in neurons to promote dendritic growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

FARP1-AS1 (HGNC:40229): (FARP1 antisense RNA 1)

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=0.11001411).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARP1	NM_005766.4	c.2244T>G	p.Ile748Met	missense_variant	Exon 19 of 27	ENST00000319562.11	NP_005757.1
FARP1	NM_001286839.2	c.2244T>G	p.Ile748Met	missense_variant	Exon 19 of 28		NP_001273768.1
FARP1-AS1	NR_046595.1	n.70-18A>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FARP1	ENST00000319562.11	c.2244T>G	p.Ile748Met	missense_variant	Exon 19 of 27	1	NM_005766.4	ENSP00000322926.6

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000286 AC: 72 AN: 251378 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000326 AC: 477 AN: 1461822 Hom.: 1 Cov.: 31 AF XY: 0.000300 AC XY: 218 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000387

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74508

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2244T>G (p.I748M) alteration is located in exon 19 (coding exon 18) of the FARP1 gene. This alteration results from a T to G substitution at nucleotide position 2244, causing the isoleucine (I) at amino acid position 748 to be replaced by a methionine (M). 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	0.093
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	.;.;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.85	.;T;T;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	.;.;N;.
REVEL	Benign	0.26
Sift	Uncertain	0.010	.;.;D;.
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		0.79	P;P;P;.
Vest4		0.52
MVP		0.65
MPC		0.53
ClinPred		0.092	T
GERP RS		-0.89
Varity_R		0.24
gMVP		0.24

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: rs140045465; hg19: chr13-99087930;