19-35269656-A-T

Position:

• chr19-35269656-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003367.4(USF2):​c.185A>T​(p.His62Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,682 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: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USF2 NM_003367.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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]

USF2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37965855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USF2	NM_003367.4	c.185A>T	p.His62Leu	missense_variant	3/10	ENST00000222305.8	NP_003358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USF2	ENST00000222305.8	c.185A>T	p.His62Leu	missense_variant	3/10	1	NM_003367.4	ENSP00000222305.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1382682 Hom.: 0 Cov.: 34 AF XY: 0.00000146 AC XY: 1 AN XY: 687076

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: 0.00000188

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.185A>T (p.H62L) alteration is located in exon 3 (coding exon 3) of the USF2 gene. This alteration results from a A to T substitution at nucleotide position 185, causing the histidine (H) at amino acid position 62 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	Benign	0.33
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.36	.;T;.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Uncertain	-0.047	T
MutationAssessor	Benign	1.8	L;L;L;L;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.8	D;N;.;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.036	D;T;.;T;.
Sift4G	Uncertain	0.041	D;T;T;T;T
Polyphen		0.23	B;P;.;.;P
Vest4		0.37
MutPred		0.37		.;.;.;.;Gain of stability (P = 0.0227);
MVP		0.65
MPC		1.8
ClinPred		0.97	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-35760559;