rs370459275

Variant names:

• chr10-13656703-G-A
• rs370459275
• NM_018027.5:c.2886C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_018027.5(FRMD4A):​c.2886C>T​(p.Ser962Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,576,268 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: FRMD4A NM_018027.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0250
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 10-13656703-G-A is Benign according to our data. Variant chr10-13656703-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 728534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.025 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.2886C>T	p.Ser962Ser	synonymous_variant	Exon 22 of 25	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2	c.2985C>T	p.Ser995Ser	synonymous_variant	Exon 21 of 24		NP_001305266.1
FRMD4A	NM_001318336.2	c.2934C>T	p.Ser978Ser	synonymous_variant	Exon 21 of 24		NP_001305265.1
FRMD4A	NM_001318338.2	c.1959C>T	p.Ser653Ser	synonymous_variant	Exon 11 of 14		NP_001305267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.2886C>T	p.Ser962Ser	synonymous_variant	Exon 22 of 25	1	NM_018027.5	ENSP00000350032.2
FRMD4A	ENST00000495956.3	c.2886C>T	p.Ser962Ser	synonymous_variant	Exon 22 of 24	2		ENSP00000488764.2
PRPF18	ENST00000593351.2	n.47+8473G>A		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 30 AN: 216346 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000678

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000909

Gnomad OTH exome AF: 0.000200

GnomAD4 exome AF: 0.000147 AC: 210 AN: 1424038 Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 108 AN XY: 708006

African (AFR) AF: 0.00 AC: 0 AN: 30710

American (AMR) AF: 0.000617 AC: 25 AN: 40550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 35972

South Asian (SAS) AF: 0.00 AC: 0 AN: 81706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4706

European-Non Finnish (NFE) AF: 0.000164 AC: 179 AN: 1093910

Other (OTH) AF: 0.000102 AC: 6 AN: 58706

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74376

African (AFR) AF: 0.0000241 AC: 1 AN: 41480

American (AMR) AF: 0.00137 AC: 21 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

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

Alfa AF: 0.0000824 Hom.: 0

Bravo AF: 0.000208

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FRMD4A: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.9
DANN	Benign	0.89
PhyloP100		0.025
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs370459275; hg19: chr10-13698703; COSMIC: COSV62268168; COSMIC: COSV62268168;