7-23691567-G-T

Variant names:

• chr7-23691567-G-T
• rs1282305046
• NM_199136.5:c.608G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_199136.5(FAM221A):​c.608G>T​(p.Gly203Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM221A NM_199136.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.33

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM221A	NM_199136.5	c.608G>T	p.Gly203Val	missense_variant	Exon 4 of 7	ENST00000344962.9	NP_954587.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM221A	ENST00000344962.9	c.608G>T	p.Gly203Val	missense_variant	Exon 4 of 7	1	NM_199136.5	ENSP00000342576.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.608G>T (p.G203V) alteration is located in exon 4 (coding exon 4) of the FAM221A gene. This alteration results from a G to T substitution at nucleotide position 608, causing the glycine (G) at amino acid position 203 to be replaced by a valine (V). 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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	.;T;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.1	M;M;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.3	D;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.89
MutPred		0.54		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;.;
MVP		0.28
MPC		0.44
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs1282305046; hg19: chr7-23731186;