10-13693947-A-G

Variant names:

• chr10-13693947-A-G
• rs2296596
• NM_018027.5:c.1068T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_018027.5(FRMD4A):​c.1068T>C​(p.Gly356Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,596,308 control chromosomes in the GnomAD database, including 9,824 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1272 hom., cov: 30)
  • Exomes 𝑓: 0.11 (8552 hom.)
• Consequence: FRMD4A NM_018027.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.496
• Publications: 11 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]

FRMD4A Gene-Disease associations (from GenCC):

• severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP7: Synonymous conserved (PhyloP=-0.496 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.1068T>C	p.Gly356Gly	synonymous_variant	Exon 15 of 25	ENST00000357447.7	NP_060497.3
FRMD4A	NM_001318337.2	c.1167T>C	p.Gly389Gly	synonymous_variant	Exon 14 of 24		NP_001305266.1
FRMD4A	NM_001318336.2	c.1116T>C	p.Gly372Gly	synonymous_variant	Exon 14 of 24		NP_001305265.1
FRMD4A	NM_001318338.2	c.141T>C	p.Gly47Gly	synonymous_variant	Exon 4 of 14		NP_001305267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.1068T>C	p.Gly356Gly	synonymous_variant	Exon 15 of 25	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19132 AN: 150228 Hom.: 1262 Cov.: 30

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0947

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.105 AC: 24842 AN: 236660 AF XY: 0.105

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.0662

Gnomad ASJ exome AF: 0.0850

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.0881

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0990

GnomAD4 exome AF: 0.107 AC: 154823 AN: 1445960 Hom.: 8552 Cov.: 32 AF XY: 0.108 AC XY: 77578 AN XY: 718780

African (AFR) AF: 0.184 AC: 5977 AN: 32442

American (AMR) AF: 0.0696 AC: 2873 AN: 41288

Ashkenazi Jewish (ASJ) AF: 0.0892 AC: 2249 AN: 25210

East Asian (EAS) AF: 0.0959 AC: 3771 AN: 39302

South Asian (SAS) AF: 0.141 AC: 11738 AN: 83476

European-Finnish (FIN) AF: 0.0896 AC: 4751 AN: 53034

Middle Eastern (MID) AF: 0.143 AC: 812 AN: 5672

European-Non Finnish (NFE) AF: 0.105 AC: 116074 AN: 1105872

Other (OTH) AF: 0.110 AC: 6578 AN: 59664

GnomAD4 genome AF: 0.128 AC: 19181 AN: 150348 Hom.: 1272 Cov.: 30 AF XY: 0.126 AC XY: 9222 AN XY: 73338

African (AFR) AF: 0.183 AC: 7457 AN: 40790

American (AMR) AF: 0.101 AC: 1528 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 352 AN: 3464

East Asian (EAS) AF: 0.116 AC: 586 AN: 5066

South Asian (SAS) AF: 0.129 AC: 613 AN: 4734

European-Finnish (FIN) AF: 0.0947 AC: 972 AN: 10268

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.107 AC: 7244 AN: 67634

Other (OTH) AF: 0.125 AC: 260 AN: 2082

Alfa AF: 0.115 Hom.: 2346

Bravo AF: 0.131

Asia WGS AF: 0.120 AC: 419 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.2
DANN	Benign	0.70
PhyloP100		-0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=88/12	polymorphism (auto)

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: rs2296596; hg19: chr10-13735947; COSMIC: COSV52723954; COSMIC: COSV52723954;