chr6-100448367-A-T

Variant names:

• chr6-100448367-A-T
• rs3213541
• NM_005068.3:c.743+112T>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005068.3(SIM1):​c.743+112T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,389,558 control chromosomes in the GnomAD database, including 19 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 0.0059 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (13 hom.)
• Consequence: SIM1 NM_005068.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.91

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=-0.89).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00588 (895/152172) while in subpopulation AFR AF= 0.0199 (828/41540). AF 95% confidence interval is 0.0188. There are 6 homozygotes in gnomad4. There are 422 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 895 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIM1	NM_005068.3	c.743+112T>A		intron_variant	Intron 7 of 11	ENST00000369208.8	NP_005059.2
SIM1	NM_001374769.1	c.743+112T>A		intron_variant	Intron 7 of 11		NP_001361698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIM1	ENST00000369208.8	c.743+112T>A		intron_variant	Intron 7 of 11	1	NM_005068.3	ENSP00000358210.4
SIM1	ENST00000262901.4	c.743+112T>A		intron_variant	Intron 6 of 10	1		ENSP00000262901.4

Frequencies

GnomAD3 genomes AF: 0.00586 AC: 891 AN: 152054 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000769 AC: 952 AN: 1237386 Hom.: 13 Cov.: 17 AF XY: 0.000682 AC XY: 419 AN XY: 614028

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00437

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000835

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000944

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00588 AC: 895 AN: 152172 Hom.: 6 Cov.: 33 AF XY: 0.00567 AC XY: 422 AN XY: 74382

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00379

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.012
DANN	Benign	0.53

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: rs3213541; hg19: chr6-100896243;