4-1655033-C-G

Variant names:

• chr4-1655033-C-G
• rs116661726
• NM_001174070.3:c.827G>C

Variant summary

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

The NM_001174070.3(FAM53A):​c.827G>C​(p.Arg276Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,424,882 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FAM53A NM_001174070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.87
• Publications: 0 publications found

Genes affected

FAM53A (HGNC:31860): (family with sequence similarity 53 member A) Predicted to be involved in protein import into nucleus. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174070.3. 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
	FAM53A	NM_001174070.3	MANE Select	c.827G>C	p.Arg276Pro	missense	Exon 4 of 5	NP_001167541.1	Q6NSI3
	FAM53A	NM_001013622.3		c.827G>C	p.Arg276Pro	missense	Exon 4 of 5	NP_001013644.1	Q6NSI3
	FAM53A	NM_001297435.1		c.827G>C	p.Arg276Pro	missense	Exon 4 of 6	NP_001284364.1	C9JYQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM53A	ENST00000308132.11	TSL:2 MANE Select	c.827G>C	p.Arg276Pro	missense	Exon 4 of 5	ENSP00000310057.6	Q6NSI3
	FAM53A	ENST00000472884.6	TSL:1	c.827G>C	p.Arg276Pro	missense	Exon 4 of 5	ENSP00000426260.1	Q6NSI3
	FAM53A	ENST00000461064.5	TSL:2	c.827G>C	p.Arg276Pro	missense	Exon 3 of 4	ENSP00000418243.1	Q6NSI3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000452 AC: 1 AN: 221478 AF XY: 0.00000830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000342

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424882 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 705892

African (AFR) AF: 0.00 AC: 0 AN: 31462

American (AMR) AF: 0.0000252 AC: 1 AN: 39658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24274

East Asian (EAS) AF: 0.00 AC: 0 AN: 38512

South Asian (SAS) AF: 0.00 AC: 0 AN: 80646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093704

Other (OTH) AF: 0.00 AC: 0 AN: 58720

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.43		Gain of methylation at K273 (P = 0.0718)
MVP		0.42
MPC		0.57
ClinPred		0.99	D
GERP RS		2.8
PromoterAI		0.077	Neutral
Varity_R		0.70
gMVP		0.19
Mutation Taster		=70/30	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: rs116661726; hg19: chr4-1656760;