6-100390310-C-T

Position:

• chr6-100390310-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_005068.3(SIM1):​c.*51G>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 0.00206 in 1,567,458 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: SIM1 NM_005068.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.631

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-100390310-C-T is Benign according to our data. Variant chr6-100390310-C-T is described in ClinVar as [Benign]. Clinvar id is 354674.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1638/152286) while in subpopulation AFR AF= 0.0375 (1559/41560). AF 95% confidence interval is 0.036. There are 33 homozygotes in gnomad4. There are 771 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1638 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIM1	NM_005068.3	c.*51G>A		3_prime_UTR_variant	12/12	ENST00000369208.8
SIM1	NM_001374769.1	c.*51G>A		3_prime_UTR_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM1	ENST00000369208.8	c.*51G>A		3_prime_UTR_variant	12/12	1	NM_005068.3	P1
SIM1	ENST00000262901.4	c.*51G>A		3_prime_UTR_variant	11/11	1		P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1624 AN: 152168 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00310 AC: 666 AN: 214862 Hom.: 18 AF XY: 0.00242 AC XY: 277 AN XY: 114294

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.0000472

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.00113 AC: 1597 AN: 1415172 Hom.: 25 Cov.: 28 AF XY: 0.00103 AC XY: 720 AN XY: 699642

Gnomad4 AFR exome AF: 0.0361

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000910

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.0108 AC: 1638 AN: 152286 Hom.: 33 Cov.: 32 AF XY: 0.0104 AC XY: 771 AN XY: 74464

Gnomad4 AFR AF: 0.0375

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00414 Hom.: 2

Bravo AF: 0.0129

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Obesity due to SIM1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs55805997; hg19: chr6-100838186;