rs1296396351

Variant names:

• chr10-13656707-G-A
• rs1296396351
• NM_018027.5:c.2882C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-13656707-G-A
• chr10-13656707-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018027.5(FRMD4A):​c.2882C>T​(p.Thr961Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000758 in 1,583,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: FRMD4A NM_018027.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.12
• Publications: 0 publications found

Genes affected

FRMD4A (HGNC:25491): (FERM domain containing 4A) This gene encodes a FERM domain-containing protein that regulates epithelial cell polarity. It connects ADP ribosylation factor 6 (ARF6) with the Par protein complex, which regulates the remodeling of adherens junctions and linear actin cable formation during epithelial cell polarization. Polymorphisms in this gene are associated with Alzheimer's disease, and also with nicotine dependence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

PRPF18 (HGNC:17351): (pre-mRNA processing factor 18) Pre-mRNA splicing occurs in 2 sequential transesterification steps. The protein encoded by this gene is found to be essential for the catalytic step II in pre-mRNA splicing process. It is found in the spliceosome, and contains seven WD repeats, which function in protein-protein interactions. This protein has a sequence similarity to the yeast splicing factor Prp18. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18898955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018027.5. 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
	FRMD4A	NM_018027.5	MANE Select	c.2882C>T	p.Thr961Ile	missense	Exon 22 of 25	NP_060497.3
	FRMD4A	NM_001318337.2		c.2981C>T	p.Thr994Ile	missense	Exon 21 of 24	NP_001305266.1
	FRMD4A	NM_001318336.2		c.2930C>T	p.Thr977Ile	missense	Exon 21 of 24	NP_001305265.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD4A	ENST00000357447.7	TSL:1 MANE Select	c.2882C>T	p.Thr961Ile	missense	Exon 22 of 25	ENSP00000350032.2	Q9P2Q2
	FRMD4A	ENST00000495956.3	TSL:2	c.2882C>T	p.Thr961Ile	missense	Exon 22 of 24	ENSP00000488764.2	A0A0J9YYA7
	PRPF18	ENST00000593351.2	TSL:5	n.47+8477G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000768 AC: 11 AN: 1431662 Hom.: 0 Cov.: 31 AF XY: 0.00000562 AC XY: 4 AN XY: 711844

African (AFR) AF: 0.00 AC: 0 AN: 31048

American (AMR) AF: 0.00 AC: 0 AN: 41410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25316

East Asian (EAS) AF: 0.00 AC: 0 AN: 36468

South Asian (SAS) AF: 0.00 AC: 0 AN: 82398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4734

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1098396

Other (OTH) AF: 0.00 AC: 0 AN: 59048

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.077
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L
PhyloP100		8.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.31
Sift	Benign	0.26	T
Sift4G	Benign	0.19	T
Polyphen		0.037	B
Vest4		0.51
MutPred		0.22		Gain of sheet (P = 0.0101)
MVP		0.20
MPC		0.38
ClinPred		0.72	D
GERP RS		4.7
PromoterAI		-0.0010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.27
Mutation Taster		=80/20	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: rs1296396351; hg19: chr10-13698707;