rs397662

Variant names:

• chr6-100447468-C-T
• rs397662
• NM_005068.3:c.851-53G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-100447468-C-T
• chr6-100447468-C-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.851-53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,608,336 control chromosomes in the GnomAD database, including 608,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.89 (60476 hom., cov: 33)
  • Exomes 𝑓: 0.87 (548114 hom.)
• Consequence: SIM1 NM_005068.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.958
• Publications: 11 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
• inherited obesity

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-100447468-C-T is Benign according to our data. Variant chr6-100447468-C-T is described in ClinVar as Benign. ClinVar VariationId is 1246865.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.955 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.851-53G>A		intron	N/A	NP_005059.2
	SIM1	NM_001374769.1		c.851-53G>A		intron	N/A	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.851-53G>A		intron	N/A	ENSP00000358210.4	P81133
	SIM1	ENST00000262901.4	TSL:1	c.851-53G>A		intron	N/A	ENSP00000262901.4	P81133
	SIM1	ENST00000900753.1		c.851-53G>A		intron	N/A	ENSP00000570812.1

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135367 AN: 152136 Hom.: 60426 Cov.: 33

Gnomad AFR AF: 0.949

Gnomad AMI AF: 0.809

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.978

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.882

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.854

Gnomad OTH AF: 0.859

GnomAD4 exome AF: 0.867 AC: 1262165 AN: 1456082 Hom.: 548114 AF XY: 0.867 AC XY: 628005 AN XY: 723972

African (AFR) AF: 0.949 AC: 31701 AN: 33404

American (AMR) AF: 0.922 AC: 40900 AN: 44338

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 19168 AN: 25840

East Asian (EAS) AF: 0.981 AC: 38868 AN: 39612

South Asian (SAS) AF: 0.937 AC: 80276 AN: 85636

European-Finnish (FIN) AF: 0.877 AC: 46513 AN: 53010

Middle Eastern (MID) AF: 0.811 AC: 4666 AN: 5754

European-Non Finnish (NFE) AF: 0.855 AC: 947953 AN: 1108308

Other (OTH) AF: 0.866 AC: 52120 AN: 60180

GnomAD4 genome AF: 0.890 AC: 135467 AN: 152254 Hom.: 60476 Cov.: 33 AF XY: 0.893 AC XY: 66467 AN XY: 74442

African (AFR) AF: 0.949 AC: 39439 AN: 41554

American (AMR) AF: 0.892 AC: 13657 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2587 AN: 3472

East Asian (EAS) AF: 0.978 AC: 5056 AN: 5172

South Asian (SAS) AF: 0.937 AC: 4518 AN: 4822

European-Finnish (FIN) AF: 0.882 AC: 9360 AN: 10610

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.854 AC: 58086 AN: 68002

Other (OTH) AF: 0.851 AC: 1798 AN: 2114

Alfa AF: 0.859 Hom.: 89425

Bravo AF: 0.892

Asia WGS AF: 0.931 AC: 3237 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.86
CADD	Benign	4.1
DANN	Benign	0.24
PhyloP100		-0.96
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs397662; hg19: chr6-100895344; COSMIC: COSV53492376;