rs1395119

Variant names:

• chr6-100390013-T-A
• rs1395119
• NM_005068.3:c.*348A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-100390013-T-A
• chr6-100390013-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005068.3(SIM1):​c.*348A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 385,692 control chromosomes in the GnomAD database, including 30,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10131 hom., cov: 32)
  • Exomes 𝑓: 0.40 (20159 hom.)
• Consequence: SIM1 NM_005068.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.277
• Publications: 8 publications found

Genes affected

SIM1 (HGNC:10882): (SIM bHLH transcription factor 1) SIM1 and SIM2 genes are Drosophila single-minded (sim) gene homologs. SIM1 transcript was detected only in fetal kidney out of various adult and fetal tissues tested. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis,it was proposed that the human SIM gene is a candidate for involvement in certain dysmorphic features (particularly the facial and skull characteristics), abnormalities of brain development, and/or cognitive disability of Down syndrome. [provided by RefSeq, Jul 2008]

SIM1 Gene-Disease associations (from GenCC):

• obesity due to SIM1 deficiency

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 6-100390013-T-A is Benign according to our data. Variant chr6-100390013-T-A is described in ClinVar as Benign. ClinVar VariationId is 354670.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3	c.*348A>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1	c.*348A>T		3_prime_UTR_variant	Exon 12 of 12		NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8	c.*348A>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_005068.3	ENSP00000358210.4
SIM1	ENST00000262901.4	c.*348A>T		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000262901.4

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53386 AN: 152000 Hom.: 10109 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.395 AC: 92325 AN: 233576 Hom.: 20159 Cov.: 0 AF XY: 0.394 AC XY: 46915 AN XY: 119118

African (AFR) AF: 0.242 AC: 1681 AN: 6936

American (AMR) AF: 0.445 AC: 4091 AN: 9196

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 2521 AN: 8644

East Asian (EAS) AF: 0.755 AC: 15697 AN: 20782

South Asian (SAS) AF: 0.322 AC: 1797 AN: 5576

European-Finnish (FIN) AF: 0.397 AC: 6542 AN: 16472

Middle Eastern (MID) AF: 0.355 AC: 423 AN: 1190

European-Non Finnish (NFE) AF: 0.361 AC: 53824 AN: 149244

Other (OTH) AF: 0.370 AC: 5749 AN: 15536

GnomAD4 genome AF: 0.351 AC: 53444 AN: 152116 Hom.: 10131 Cov.: 32 AF XY: 0.357 AC XY: 26514 AN XY: 74366

African (AFR) AF: 0.246 AC: 10233 AN: 41536

American (AMR) AF: 0.430 AC: 6564 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1047 AN: 3470

East Asian (EAS) AF: 0.747 AC: 3851 AN: 5158

South Asian (SAS) AF: 0.338 AC: 1630 AN: 4822

European-Finnish (FIN) AF: 0.407 AC: 4300 AN: 10570

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24710 AN: 67964

Other (OTH) AF: 0.343 AC: 726 AN: 2114

Alfa AF: 0.360 Hom.: 1290

Bravo AF: 0.352

Asia WGS AF: 0.507 AC: 1758 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Obesity due to SIM1 deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.047
DANN	Benign	0.51
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1395119; hg19: chr6-100837889;