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: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005068.3. 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
	SIM1	NM_005068.3	MANE Select	c.*348A>T		3_prime_UTR	Exon 12 of 12	NP_005059.2
	SIM1	NM_001374769.1		c.*348A>T		3_prime_UTR	Exon 12 of 12	NP_001361698.1	P81133

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM1	ENST00000369208.8	TSL:1 MANE Select	c.*348A>T		3_prime_UTR	Exon 12 of 12	ENSP00000358210.4	P81133
	SIM1	ENST00000262901.4	TSL:1	c.*348A>T		3_prime_UTR	Exon 11 of 11	ENSP00000262901.4	P81133
	SIM1	ENST00000900753.1		c.*348A>T		3_prime_UTR	Exon 12 of 12	ENSP00000570812.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Obesity due to SIM1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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;