7-99047708-T-C

Variant names:

• chr7-99047708-T-C
• rs141532197
• NM_181349.3:c.1128A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_181349.3(SMURF1):​c.1128A>G​(p.Glu376Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,614,130 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: SMURF1 NM_181349.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.69
• Publications: 0 publications found

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]

TRRAP Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder with or without congenital anomalies

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental delay with or without dysmorphic facies and autism

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal dominant 75

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 7-99047708-T-C is Benign according to our data. Variant chr7-99047708-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2657718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.69 with no splicing effect.
• BS2: High AC in GnomAd4 at 301 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181349.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMURF1	NM_181349.3	MANE Select	c.1128A>G	p.Glu376Glu	synonymous	Exon 10 of 18	NP_851994.1	Q9HCE7-2
	SMURF1	NM_020429.3		c.1206A>G	p.Glu402Glu	synonymous	Exon 11 of 19	NP_065162.1	Q9HCE7-1
	SMURF1	NM_001199847.2		c.1128A>G	p.Glu376Glu	synonymous	Exon 10 of 18	NP_001186776.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMURF1	ENST00000361368.7	TSL:1 MANE Select	c.1128A>G	p.Glu376Glu	synonymous	Exon 10 of 18	ENSP00000355326.2	Q9HCE7-2
	SMURF1	ENST00000361125.1	TSL:1	c.1206A>G	p.Glu402Glu	synonymous	Exon 11 of 19	ENSP00000354621.1	Q9HCE7-1
	SMURF1	ENST00000885289.1		c.1206A>G	p.Glu402Glu	synonymous	Exon 11 of 19	ENSP00000555348.1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00153 AC: 385 AN: 251482 AF XY: 0.00146

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00277 AC: 4053 AN: 1461890 Hom.: 9 Cov.: 30 AF XY: 0.00268 AC XY: 1946 AN XY: 727246

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00342 AC: 3805 AN: 1112010

Other (OTH) AF: 0.00277 AC: 167 AN: 60396

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152240 Hom.: 1 Cov.: 33 AF XY: 0.00176 AC XY: 131 AN XY: 74388

African (AFR) AF: 0.000965 AC: 40 AN: 41472

American (AMR) AF: 0.000589 AC: 9 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00359 AC: 244 AN: 68040

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00216

EpiCase AF: 0.00376

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141532197; hg19: chr7-98645331;