rs74726213

Variant names:

• chr6-100390543-C-G
• rs74726213
• NM_005068.3:c.2119G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-100390543-C-G
• chr6-100390543-C-A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_005068.3(SIM1):​c.2119G>C​(p.Asp707His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: SIM1 NM_005068.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 7.57
• Publications: 8 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25757468).
• BP6: Variant 6-100390543-C-G is Benign according to our data. Variant chr6-100390543-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254101.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000565 (86/152244) while in subpopulation NFE AF = 0.00106 (72/68022). AF 95% confidence interval is 0.000861. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.2119G>C	p.Asp707His	missense	Exon 12 of 12	NP_005059.2
	SIM1	NM_001374769.1		c.2119G>C	p.Asp707His	missense	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.2119G>C	p.Asp707His	missense	Exon 12 of 12	ENSP00000358210.4	P81133
	SIM1	ENST00000262901.4	TSL:1	c.2119G>C	p.Asp707His	missense	Exon 11 of 11	ENSP00000262901.4	P81133
	SIM1	ENST00000900753.1		c.2119G>C	p.Asp707His	missense	Exon 12 of 12	ENSP00000570812.1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000517 AC: 130 AN: 251462 AF XY: 0.000530

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000976

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00115 AC: 1681 AN: 1461874 Hom.: 3 Cov.: 31 AF XY: 0.00115 AC XY: 838 AN XY: 727236

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00143 AC: 1585 AN: 1112008

Other (OTH) AF: 0.00104 AC: 63 AN: 60394

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74434

African (AFR) AF: 0.000241 AC: 10 AN: 41544

American (AMR) AF: 0.000196 AC: 3 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000578

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.00125

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Monogenic diabetes (1)
-	1	-	not specified (1)
-	1	-	Obesity due to SIM1 deficiency (1)
-	-	1	Oromandibular-limb hypogenesis spectrum (1)
-	1	-	SIM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.23	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.69
MVP		0.18
MPC		0.18
ClinPred		0.061	T
GERP RS		6.2
Varity_R		0.22
gMVP		0.72
Mutation Taster		=13/87	disease causing

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: rs74726213; hg19: chr6-100838419; COSMIC: COSV53493929; COSMIC: COSV53493929;