chr6-100448413-T-G

Variant names:

• chr6-100448413-T-G
• rs3830139
• NM_005068.3:c.743+66A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005068.3(SIM1):​c.743+66A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,518,488 control chromosomes in the GnomAD database, including 56,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5383 hom., cov: 33)
  • Exomes 𝑓: 0.27 (51297 hom.)
• Consequence: SIM1 NM_005068.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.336
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-100448413-T-G is Benign according to our data. Variant chr6-100448413-T-G is described in ClinVar as Benign. ClinVar VariationId is 1246330.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 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.743+66A>C		intron	N/A	NP_005059.2
	SIM1	NM_001374769.1		c.743+66A>C		intron	N/A	NP_001361698.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIM1	ENST00000369208.8	TSL:1 MANE Select	c.743+66A>C		intron	N/A	ENSP00000358210.4
	SIM1	ENST00000262901.4	TSL:1	c.743+66A>C		intron	N/A	ENSP00000262901.4

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39208 AN: 151998 Hom.: 5380 Cov.: 33

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.269 AC: 368171 AN: 1366372 Hom.: 51297 Cov.: 22 AF XY: 0.267 AC XY: 181044 AN XY: 677388

African (AFR) AF: 0.186 AC: 5795 AN: 31120

American (AMR) AF: 0.405 AC: 15587 AN: 38534

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5111 AN: 24082

East Asian (EAS) AF: 0.429 AC: 16002 AN: 37314

South Asian (SAS) AF: 0.212 AC: 16905 AN: 79682

European-Finnish (FIN) AF: 0.311 AC: 15766 AN: 50740

Middle Eastern (MID) AF: 0.282 AC: 1299 AN: 4614

European-Non Finnish (NFE) AF: 0.265 AC: 276591 AN: 1043562

Other (OTH) AF: 0.266 AC: 15115 AN: 56724

GnomAD4 genome AF: 0.258 AC: 39227 AN: 152116 Hom.: 5383 Cov.: 33 AF XY: 0.263 AC XY: 19562 AN XY: 74342

African (AFR) AF: 0.189 AC: 7863 AN: 41498

American (AMR) AF: 0.348 AC: 5319 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 711 AN: 3468

East Asian (EAS) AF: 0.400 AC: 2065 AN: 5166

South Asian (SAS) AF: 0.212 AC: 1022 AN: 4820

European-Finnish (FIN) AF: 0.323 AC: 3406 AN: 10560

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17953 AN: 67994

Other (OTH) AF: 0.241 AC: 510 AN: 2114

Alfa AF: 0.254 Hom.: 826

Bravo AF: 0.262

Asia WGS AF: 0.280 AC: 974 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.1
DANN	Benign	0.51
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3830139; hg19: chr6-100896289; COSMIC: COSV53490118;