chr6-100448367-A-G

Variant names:

• chr6-100448367-A-G
• rs3213541
• NM_005068.3:c.743+112T>C

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.743+112T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,387,752 control chromosomes in the GnomAD database, including 51,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5343 hom., cov: 33)
  • Exomes 𝑓: 0.27 (46624 hom.)
• Consequence: SIM1 NM_005068.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.91
• Publications: 7 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=-0.9).
• BP6: Variant 6-100448367-A-G is Benign according to our data. Variant chr6-100448367-A-G is described in ClinVar as Benign. ClinVar VariationId is 1273352.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 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.743+112T>C		intron	N/A	NP_005059.2
	SIM1	NM_001374769.1		c.743+112T>C		intron	N/A	NP_001361698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM1	ENST00000369208.8	TSL:1 MANE Select	c.743+112T>C		intron	N/A	ENSP00000358210.4
	SIM1	ENST00000262901.4	TSL:1	c.743+112T>C		intron	N/A	ENSP00000262901.4
	SIM1	ENST00000900753.1		c.743+112T>C		intron	N/A	ENSP00000570812.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39030 AN: 152014 Hom.: 5342 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.270 AC: 333011 AN: 1235620 Hom.: 46624 Cov.: 17 AF XY: 0.267 AC XY: 163793 AN XY: 613188

African (AFR) AF: 0.180 AC: 5119 AN: 28390

American (AMR) AF: 0.399 AC: 13484 AN: 33796

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 4630 AN: 21950

East Asian (EAS) AF: 0.431 AC: 15122 AN: 35124

South Asian (SAS) AF: 0.211 AC: 15160 AN: 71816

European-Finnish (FIN) AF: 0.310 AC: 14533 AN: 46890

Middle Eastern (MID) AF: 0.285 AC: 1270 AN: 4452

European-Non Finnish (NFE) AF: 0.265 AC: 249782 AN: 940990

Other (OTH) AF: 0.266 AC: 13911 AN: 52212

GnomAD4 genome AF: 0.257 AC: 39043 AN: 152132 Hom.: 5343 Cov.: 33 AF XY: 0.262 AC XY: 19457 AN XY: 74364

African (AFR) AF: 0.185 AC: 7665 AN: 41530

American (AMR) AF: 0.347 AC: 5311 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3470

East Asian (EAS) AF: 0.400 AC: 2060 AN: 5156

South Asian (SAS) AF: 0.212 AC: 1024 AN: 4826

European-Finnish (FIN) AF: 0.322 AC: 3405 AN: 10580

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 17976 AN: 67962

Other (OTH) AF: 0.242 AC: 511 AN: 2112

Alfa AF: 0.222 Hom.: 2337

Bravo AF: 0.261

ClinVar

ClinVar submissions as Germline

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	-0.90
CADD	Benign	0.013
DANN	Benign	0.30
PhyloP100		-2.9
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: rs3213541; hg19: chr6-100896243; COSMIC: COSV53493190;