rs219825

Variant names:

• chr7-99047942-C-G
• rs219825
• NM_181349.3:c.954-60G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181349.3(SMURF1):​c.954-60G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,525,540 control chromosomes in the GnomAD database, including 120,878 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (18841 hom., cov: 33)
  • Exomes 𝑓: 0.38 (102037 hom.)
• Consequence: SMURF1 NM_181349.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.484
• Publications: 4 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: Illumina, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMURF1	NM_181349.3	c.954-60G>C		intron_variant	Intron 9 of 17	ENST00000361368.7	NP_851994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMURF1	ENST00000361368.7	c.954-60G>C		intron_variant	Intron 9 of 17	1	NM_181349.3	ENSP00000355326.2
SMURF1	ENST00000361125.1	c.1032-60G>C		intron_variant	Intron 10 of 18	1		ENSP00000354621.1
TRRAP	ENST00000468960.3	n.1009C>G		non_coding_transcript_exon_variant	Exon 5 of 5	4
TRRAP	ENST00000482799.3	n.1092C>G		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70889 AN: 152040 Hom.: 18803 Cov.: 33

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.465

GnomAD4 exome AF: 0.381 AC: 523085 AN: 1373382 Hom.: 102037 Cov.: 22 AF XY: 0.381 AC XY: 262246 AN XY: 687454

African (AFR) AF: 0.765 AC: 24635 AN: 32210

American (AMR) AF: 0.332 AC: 14743 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10034 AN: 25588

East Asian (EAS) AF: 0.377 AC: 14824 AN: 39298

South Asian (SAS) AF: 0.455 AC: 38461 AN: 84438

European-Finnish (FIN) AF: 0.329 AC: 14747 AN: 44802

Middle Eastern (MID) AF: 0.400 AC: 1637 AN: 4088

European-Non Finnish (NFE) AF: 0.366 AC: 380867 AN: 1041016

Other (OTH) AF: 0.402 AC: 23137 AN: 57502

GnomAD4 genome AF: 0.467 AC: 70989 AN: 152158 Hom.: 18841 Cov.: 33 AF XY: 0.463 AC XY: 34449 AN XY: 74372

African (AFR) AF: 0.747 AC: 31023 AN: 41544

American (AMR) AF: 0.360 AC: 5501 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1328 AN: 3472

East Asian (EAS) AF: 0.420 AC: 2175 AN: 5182

South Asian (SAS) AF: 0.465 AC: 2244 AN: 4826

European-Finnish (FIN) AF: 0.326 AC: 3445 AN: 10574

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23929 AN: 67974

Other (OTH) AF: 0.471 AC: 995 AN: 2114

Alfa AF: 0.413 Hom.: 1803

Bravo AF: 0.482

Asia WGS AF: 0.486 AC: 1691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.8
DANN	Benign	0.56
PhyloP100		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs219825; hg19: chr7-98645565; COSMIC: COSV63155762; COSMIC: COSV63155762;