chr6-100388760-A-T

Variant names:

• chr6-100388760-A-T
• rs17060480
• NM_005068.3:c.*1601T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005068.3(SIM1):​c.*1601T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,124 control chromosomes in the GnomAD database, including 4,294 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 0.21 (4294 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: SIM1 NM_005068.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 6 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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM1	NM_005068.3	MANE Select	c.*1601T>A		3_prime_UTR	Exon 12 of 12	NP_005059.2
	SIM1	NM_001374769.1		c.*1601T>A		3_prime_UTR	Exon 12 of 12	NP_001361698.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM1	ENST00000369208.8	TSL:1 MANE Select	c.*1601T>A		3_prime_UTR	Exon 12 of 12	ENSP00000358210.4
	SIM1	ENST00000262901.4	TSL:1	c.*1601T>A		downstream_gene	N/A	ENSP00000262901.4

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31465 AN: 152006 Hom.: 4287 Cov.: 32

Gnomad AFR AF: 0.0554

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.192

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.207 AC: 31483 AN: 152124 Hom.: 4294 Cov.: 32 AF XY: 0.215 AC XY: 16005 AN XY: 74346

African (AFR) AF: 0.0555 AC: 2305 AN: 41546

American (AMR) AF: 0.283 AC: 4327 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 597 AN: 3470

East Asian (EAS) AF: 0.594 AC: 3074 AN: 5174

South Asian (SAS) AF: 0.265 AC: 1277 AN: 4810

European-Finnish (FIN) AF: 0.320 AC: 3379 AN: 10572

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15847 AN: 67962

Other (OTH) AF: 0.191 AC: 403 AN: 2108

Alfa AF: 0.217 Hom.: 470

Bravo AF: 0.201

Asia WGS AF: 0.360 AC: 1250 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.7
DANN	Benign	0.77
PhyloP100		1.6
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: rs17060480; hg19: chr6-100836636;