chr6-100389424-G-T

Variant names:

• chr6-100389424-G-T
• rs41318037
• NM_005068.3:c.*937C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005068.3(SIM1):​c.*937C>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 0.0069 in 392,600 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (10 hom.)
• Consequence: SIM1 NM_005068.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.554
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-100389424-G-T is Benign according to our data. Variant chr6-100389424-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 905432.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00645 (981/152058) while in subpopulation NFE AF = 0.00727 (494/67956). AF 95% confidence interval is 0.00674. There are 12 homozygotes in GnomAd4. There are 552 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.*937C>A		3_prime_UTR	Exon 12 of 12	NP_005059.2
	SIM1	NM_001374769.1		c.*937C>A		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.*937C>A		3_prime_UTR	Exon 12 of 12	ENSP00000358210.4	P81133
	SIM1	ENST00000262901.4	TSL:1	c.*937C>A		3_prime_UTR	Exon 11 of 11	ENSP00000262901.4	P81133
	SIM1	ENST00000900753.1		c.*937C>A		3_prime_UTR	Exon 12 of 12	ENSP00000570812.1

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 981 AN: 151940 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00727

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00718 AC: 1726 AN: 240542 Hom.: 10 Cov.: 0 AF XY: 0.00706 AC XY: 861 AN XY: 122016

African (AFR) AF: 0.000844 AC: 6 AN: 7108

American (AMR) AF: 0.000819 AC: 6 AN: 7322

Ashkenazi Jewish (ASJ) AF: 0.000110 AC: 1 AN: 9120

East Asian (EAS) AF: 0.00 AC: 0 AN: 22598

South Asian (SAS) AF: 0.000928 AC: 2 AN: 2156

European-Finnish (FIN) AF: 0.0272 AC: 551 AN: 20226

Middle Eastern (MID) AF: 0.000790 AC: 1 AN: 1266

European-Non Finnish (NFE) AF: 0.00706 AC: 1092 AN: 154672

Other (OTH) AF: 0.00417 AC: 67 AN: 16074

GnomAD4 genome AF: 0.00645 AC: 981 AN: 152058 Hom.: 12 Cov.: 32 AF XY: 0.00743 AC XY: 552 AN XY: 74334

African (AFR) AF: 0.00154 AC: 64 AN: 41468

American (AMR) AF: 0.00131 AC: 20 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4806

European-Finnish (FIN) AF: 0.0372 AC: 393 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00727 AC: 494 AN: 67956

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00485 Hom.: 1

Bravo AF: 0.00382

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

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	-0.90
CADD	Benign	0.28
DANN	Benign	0.35
PhyloP100		0.55
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: rs41318037; hg19: chr6-100837300;