NM_199136.5:c.73G>A

Variant names:

• chr7-23684506-G-A
• NM_199136.5:c.73G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_199136.5(FAM221A):​c.73G>A​(p.Gly25Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM221A NM_199136.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.62

Genes affected

FAM221A (HGNC:27977): (family with sequence similarity 221 member A)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM221A	NM_199136.5	c.73G>A	p.Gly25Ser	missense_variant	Exon 2 of 7	ENST00000344962.9	NP_954587.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM221A	ENST00000344962.9	c.73G>A	p.Gly25Ser	missense_variant	Exon 2 of 7	1	NM_199136.5	ENSP00000342576.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73G>A (p.G25S) alteration is located in exon 2 (coding exon 2) of the FAM221A gene. This alteration results from a G to A substitution at nucleotide position 73, causing the glycine (G) at amino acid position 25 to be replaced by a serine (S). 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	0.34
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	.;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.38		Gain of phosphorylation at G25 (P = 0.023);Gain of phosphorylation at G25 (P = 0.023);
MVP		0.39
MPC		0.43
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.49		Position offset: -7

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: chr7-23724125;