10-14101637-T-G

Variant names:

• chr10-14101637-T-G
• rs7921545
• NM_018027.5:c.45+228421A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018027.5(FRMD4A):​c.45+228421A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,966 control chromosomes in the GnomAD database, including 23,704 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 0.54 (23704 hom., cov: 31)
• Consequence: FRMD4A NM_018027.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD4A	NM_018027.5	c.45+228421A>C		intron_variant	Intron 2 of 24	ENST00000357447.7	NP_060497.3
FRMD4A	NR_134578.2	n.455-4499A>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD4A	ENST00000357447.7	c.45+228421A>C		intron_variant	Intron 2 of 24	1	NM_018027.5	ENSP00000350032.2

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82132 AN: 151848 Hom.: 23707 Cov.: 31

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.564

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.541 AC: 82160 AN: 151966 Hom.: 23704 Cov.: 31 AF XY: 0.541 AC XY: 40203 AN XY: 74288

African (AFR) AF: 0.331 AC: 13721 AN: 41442

American (AMR) AF: 0.460 AC: 7017 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2351 AN: 3466

East Asian (EAS) AF: 0.713 AC: 3683 AN: 5166

South Asian (SAS) AF: 0.602 AC: 2897 AN: 4810

European-Finnish (FIN) AF: 0.685 AC: 7231 AN: 10560

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43189 AN: 67938

Other (OTH) AF: 0.566 AC: 1195 AN: 2112

Alfa AF: 0.610 Hom.: 18206

Bravo AF: 0.515

Asia WGS AF: 0.580 AC: 2018 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.037
DANN	Benign	0.47
PhyloP100		-1.9
Mutation Taster		=100/0	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: rs7921545; hg19: chr10-14143636;