chr19-35269656-A-G

Position:

• chr19-35269656-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003367.4(USF2):​c.185A>G​(p.His62Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,382,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H62L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000051 (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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USF2	NM_003367.4	c.185A>G	p.His62Arg	missense_variant	3/10	ENST00000222305.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USF2	ENST00000222305.8	c.185A>G	p.His62Arg	missense_variant	3/10	1	NM_003367.4	P3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000506 AC: 7 AN: 1382682 Hom.: 0 Cov.: 34 AF XY: 0.00000728 AC XY: 5 AN XY: 687076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000239

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: 0.00000563

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

Alfa AF: 0.0000937 Hom.: 0

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 24, 2022

The c.185A>G (p.H62R) alteration is located in exon 3 (coding exon 3) of the USF2 gene. This alteration results from a A to G substitution at nucleotide position 185, causing the histidine (H) at amino acid position 62 to be replaced by an arginine (R). 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	0.19
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.95
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.91	D;T;T;D;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.8	L;L;L;L;.
MutationTaster	Benign	0.99	D;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.5	N;N;.;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.12	T;T;.;T;.
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.42	B;P;.;.;P
Vest4		0.45
MutPred		0.36		.;.;.;.;Gain of MoRF binding (P = 0.014);
MVP		0.57
MPC		1.8
ClinPred		0.76	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.25

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: rs1303724217; hg19: chr19-35760559;