22-38607472-G-C

Variant names:

• chr22-38607472-G-C
• NM_001013647.2:c.1043C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001013647.2(FAM227A):​c.1043C>G​(p.Ser348Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM227A NM_001013647.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.184

Genes affected

FAM227A (HGNC:44197): (family with sequence similarity 227 member A)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity F227A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10915148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227A	NM_001013647.2	c.1043C>G	p.Ser348Cys	missense_variant	Exon 12 of 17	ENST00000535113.7	NP_001013669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM227A	ENST00000535113.7	c.1043C>G	p.Ser348Cys	missense_variant	Exon 12 of 17	5	NM_001013647.2	ENSP00000445093.1
FAM227A	ENST00000355830.11	c.1043C>G	p.Ser348Cys	missense_variant	Exon 12 of 19	5		ENSP00000348086.7
FAM227A	ENST00000540952.6	c.1043C>G	p.Ser348Cys	missense_variant	Exon 12 of 17	5		ENSP00000493504.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396158 Hom.: 0 Cov.: 29 AF XY: 0.00000290 AC XY: 2 AN XY: 688872

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.29e-7

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1043C>G (p.S348C) alteration is located in exon 12 (coding exon 11) of the FAM227A gene. This alteration results from a C to G substitution at nucleotide position 1043, causing the serine (S) at amino acid position 348 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.9
DANN	Benign	0.61
DEOGEN2	Benign	0.0081	T;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.26	T;.;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.048
Sift	Benign	0.10	T;T;.
Sift4G	Benign	0.20	T;T;.
Polyphen		0.92	P;.;.
Vest4		0.20
MutPred		0.25		Loss of phosphorylation at S348 (P = 0.0061);.;Loss of phosphorylation at S348 (P = 0.0061);
MVP		0.014
ClinPred		0.47	T
GERP RS		0.23
Varity_R		0.055

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-39003477;