19-35269912-C-G

Variant names:

• chr19-35269912-C-G
• rs1191306963
• NM_003367.4:c.338C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003367.4(USF2):​c.338C>G​(p.Ala113Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,224,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: USF2 NM_003367.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

Genes affected

USF2 (HGNC:12594): (upstream transcription factor 2, c-fos interacting) This gene encodes a member of the basic helix-loop-helix leucine zipper family of transcription factors. The encoded protein can activate transcription through pyrimidine-rich initiator (Inr) elements and E-box motifs and is involved in regulating multiple cellular processes. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3130201).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USF2	NM_003367.4	c.338C>G	p.Ala113Gly	missense_variant	Exon 4 of 10	ENST00000222305.8	NP_003358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USF2	ENST00000222305.8	c.338C>G	p.Ala113Gly	missense_variant	Exon 4 of 10	1	NM_003367.4	ENSP00000222305.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000180 AC: 22 AN: 1224534 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 9 AN XY: 594996

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: 0.0000219

Gnomad4 OTH exome AF: 0.00

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

Oct 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.338C>G (p.A113G) alteration is located in exon 4 (coding exon 4) of the USF2 gene. This alteration results from a C to G substitution at nucleotide position 338, causing the alanine (A) at amino acid position 113 to be replaced by a glycine (G). 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	0.13
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.5	N;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.050	D;.;.
Sift4G	Uncertain	0.045	D;D;D
Polyphen		0.82	P;.;P
Vest4		0.31
MutPred		0.23		.;.;Loss of sheet (P = 0.007);
MVP		0.42
MPC		1.6
ClinPred		0.88	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1191306963; hg19: chr19-35760815;