chr6-100448367-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005068.3(SIM1):​c.743+112T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,389,558 control chromosomes in the GnomAD database, including 19 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 0.0059 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (13 hom.)
• Consequence: SIM1 NM_005068.3 intron
• Clinical Significance: Not reported in ClinVar
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00588 (895/152172) while in subpopulation AFR AF = 0.0199 (828/41540). AF 95% confidence interval is 0.0188. There are 6 homozygotes in GnomAd4. There are 422 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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>A		intron	N/A	NP_005059.2
	SIM1	NM_001374769.1		c.743+112T>A		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>A		intron	N/A	ENSP00000358210.4
	SIM1	ENST00000262901.4	TSL:1	c.743+112T>A		intron	N/A	ENSP00000262901.4
	SIM1	ENST00000900753.1		c.743+112T>A		intron	N/A	ENSP00000570812.1

Frequencies

GnomAD3 genomes AF: 0.00586 AC: 891 AN: 152054 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000769 AC: 952 AN: 1237386 Hom.: 13 Cov.: 17 AF XY: 0.000682 AC XY: 419 AN XY: 614028

African (AFR) AF: 0.0210 AC: 596 AN: 28406

American (AMR) AF: 0.00186 AC: 63 AN: 33820

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 96 AN: 21964

East Asian (EAS) AF: 0.00 AC: 0 AN: 35138

South Asian (SAS) AF: 0.0000835 AC: 6 AN: 71870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46954

Middle Eastern (MID) AF: 0.00247 AC: 11 AN: 4454

European-Non Finnish (NFE) AF: 0.0000944 AC: 89 AN: 942518

Other (OTH) AF: 0.00174 AC: 91 AN: 52262

GnomAD4 genome AF: 0.00588 AC: 895 AN: 152172 Hom.: 6 Cov.: 33 AF XY: 0.00567 AC XY: 422 AN XY: 74382

African (AFR) AF: 0.0199 AC: 828 AN: 41540

American (AMR) AF: 0.00222 AC: 34 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67978

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00 Hom.: 2337

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.012
DANN	Benign	0.53
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism

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;