rs1859626437

Variant names:

• chr9-93497587-C-G
• rs1859626437
• NM_014612.5:c.921C>G

Variant summary

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

The NM_014612.5(FAM120A):​c.921C>G​(p.Phe307Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FAM120A NM_014612.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

Genes affected

FAM120A (HGNC:13247): (family with sequence similarity 120 member A) Enables RNA binding activity. Located in cytosol. [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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM120A	NM_014612.5	c.921C>G	p.Phe307Leu	missense_variant	Exon 4 of 18	ENST00000277165.11	NP_055427.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM120A	ENST00000277165.11	c.921C>G	p.Phe307Leu	missense_variant	Exon 4 of 18	1	NM_014612.5	ENSP00000277165.5
FAM120A	ENST00000375389.7	c.921C>G	p.Phe307Leu	missense_variant	Exon 4 of 9	1		ENSP00000364538.3
FAM120A	ENST00000698944.1	c.921C>G	p.Phe307Leu	missense_variant	Exon 4 of 18			ENSP00000514050.1
FAM120A	ENST00000446420.2	c.453C>G	p.Phe151Leu	missense_variant	Exon 4 of 10	5		ENSP00000396534.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450394 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721586

African (AFR) AF: 0.00 AC: 0 AN: 32314

American (AMR) AF: 0.00 AC: 0 AN: 40884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 84220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108480

Other (OTH) AF: 0.00 AC: 0 AN: 59958

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.921C>G (p.F307L) alteration is located in exon 4 (coding exon 4) of the FAM120A gene. This alteration results from a C to G substitution at nucleotide position 921, causing the phenylalanine (F) at amino acid position 307 to be replaced by a leucine (L). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.8	M;M;.
PhyloP100		2.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	D;D;.
REVEL	Uncertain	0.29
Sift	Benign	0.13	T;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.85
MutPred		0.35		Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;
MVP		0.58
MPC		2.0
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.69
Mutation Taster		=53/47	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

Publications

LitVar

Other links and lift over

dbSNP: rs1859626437; hg19: chr9-96259869;