rs2288073

Positions:

• chr2-24190429-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040710.3(FAM228A):​c.419A>G​(p.Tyr140Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,612,508 control chromosomes in the GnomAD database, including 70,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (5069 hom., cov: 32)
  • Exomes 𝑓: 0.29 (65738 hom.)
• Consequence: FAM228A NM_001040710.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.655

Genes affected

FAM228A (HGNC:34418): (family with sequence similarity 228 member A)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004767984).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM228A	NM_001040710.3	c.419A>G	p.Tyr140Cys	missense_variant	6/6	ENST00000295150.8	NP_001035800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM228A	ENST00000295150.8	c.419A>G	p.Tyr140Cys	missense_variant	6/6	1	NM_001040710.3	ENSP00000295150
FAM228A	ENST00000432434.2	c.536A>G	p.Tyr179Cys	missense_variant	6/7	5		ENSP00000412833	P1
FAM228A	ENST00000415196.1	c.122A>G	p.Tyr41Cys	missense_variant	2/3	2		ENSP00000416595
FAM228A	ENST00000456591.6	c.*285A>G		3_prime_UTR_variant, NMD_transcript_variant	7/8	3		ENSP00000401257

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37245 AN: 152044 Hom.: 5064 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.256 AC: 63488 AN: 247650 Hom.: 8832 AF XY: 0.266 AC XY: 35741 AN XY: 134392

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.191

Gnomad SAS exome AF: 0.309

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.295 AC: 430630 AN: 1460346 Hom.: 65738 Cov.: 34 AF XY: 0.296 AC XY: 214994 AN XY: 726506

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.304

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.245 AC: 37260 AN: 152162 Hom.: 5069 Cov.: 32 AF XY: 0.244 AC XY: 18179 AN XY: 74400

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.281

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.232

Alfa AF: 0.285 Hom.: 15920

Bravo AF: 0.233

TwinsUK AF: 0.309 AC: 1145

ALSPAC AF: 0.316 AC: 1216

ESP6500AA AF: 0.163 AC: 607

ESP6500EA AF: 0.291 AC: 2376

ExAC AF: 0.259 AC: 31313

Asia WGS AF: 0.217 AC: 758 AN: 3478

EpiCase AF: 0.298

EpiControl AF: 0.299

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.31
DANN	Benign	0.53
DEOGEN2	Benign	0.0049	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00067	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	2.5	N;N
REVEL	Benign	0.062
Sift	Benign	0.83	T;T
Sift4G	Benign	0.087	T;T
Polyphen		0.0	B;.
Vest4		0.044
MPC		0.064
ClinPred		0.00016	T
GERP RS		-1.3
Varity_R		0.032
gMVP		0.0048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2288073; hg19: chr2-24413298; COSMIC: COSV54596057;