7-99040496-G-A

Position:

• chr7-99040496-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BS2

The NM_181349.3(SMURF1):​c.1432C>T​(p.His478Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,431,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SMURF1 NM_181349.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

SMURF1 (HGNC:16807): (SMAD specific E3 ubiquitin protein ligase 1) This gene encodes a ubiquitin ligase that is specific for receptor-regulated SMAD proteins in the bone morphogenetic protein (BMP) pathway. This protein plays a key roll in the regulation of cell motility, cell signalling, and cell polarity. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Dec 2010]

TRRAP (HGNC:12347): (transformation/transcription domain associated protein) This gene encodes a large multidomain protein of the phosphoinositide 3-kinase-related kinases (PIKK) family. The encoded protein is a common component of many histone acetyltransferase (HAT) complexes and plays a role in transcription and DNA repair by recruiting HAT complexes to chromatin. Deregulation of this gene may play a role in several types of cancer including glioblastoma multiforme. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMURF1	NM_181349.3	c.1432C>T	p.His478Tyr	missense_variant	13/18	ENST00000361368.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMURF1	ENST00000361368.7	c.1432C>T	p.His478Tyr	missense_variant	13/18	1	NM_181349.3	P1
SMURF1	ENST00000361125.1	c.1510C>T	p.His504Tyr	missense_variant	14/19	1
TRRAP	ENST00000468960.3	n.722-7159G>A		intron_variant, non_coding_transcript_variant		4
TRRAP	ENST00000482799.3	n.554-5046G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000349 AC: 5 AN: 1431014 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 711332

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: 0.00000456

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

May 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.58
Sift	Benign	0.057	T;D
Sift4G	Benign	0.071	T;T
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.61		.;Loss of helix (P = 0.2022);
MVP		0.76
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.61
gMVP		0.71

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: rs912509725; hg19: chr7-98638119;