NM_005068.3:c.*521A>G

Variant names:

• chr6-100389840-T-C
• rs1770591929
• NM_005068.3:c.*521A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005068.3(SIM1):​c.*521A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000406 in 246,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SIM1 NM_005068.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.*521A>G		3_prime_UTR	Exon 12 of 12	NP_005059.2
	SIM1	NM_001374769.1		c.*521A>G		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.*521A>G		3_prime_UTR	Exon 12 of 12	ENSP00000358210.4	P81133
	SIM1	ENST00000262901.4	TSL:1	c.*521A>G		3_prime_UTR	Exon 11 of 11	ENSP00000262901.4	P81133
	SIM1	ENST00000900753.1		c.*521A>G		3_prime_UTR	Exon 12 of 12	ENSP00000570812.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000406 AC: 1 AN: 246368 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124918

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 7174

American (AMR) AF: 0.00 AC: 0 AN: 7574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9222

East Asian (EAS) AF: 0.00 AC: 0 AN: 22874

South Asian (SAS) AF: 0.00 AC: 0 AN: 2414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1288

European-Non Finnish (NFE) AF: 0.00000632 AC: 1 AN: 158328

Other (OTH) AF: 0.00 AC: 0 AN: 16354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.83
CADD	Benign	9.1
DANN	Benign	0.80
PhyloP100		1.7

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: rs1770591929; hg19: chr6-100837716;