6-100420903-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005068.3(SIM1):c.1054C>G(p.Pro352Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P352S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIM1 NM_005068.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.19

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-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30720595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIM1	NM_005068.3	c.1054C>G	p.Pro352Ala	missense_variant	10/12	ENST00000369208.8
SIM1-AS1	XR_942815.4	n.891-6215G>C		intron_variant, non_coding_transcript_variant
SIM1	NM_001374769.1	c.1054C>G	p.Pro352Ala	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIM1	ENST00000369208.8	c.1054C>G	p.Pro352Ala	missense_variant	10/12	1	NM_005068.3	P1
SIM1	ENST00000262901.4	c.1054C>G	p.Pro352Ala	missense_variant	9/11	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.094	T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.14	N;N
MutationTaster	Benign	0.0000026	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.12
Sift	Benign	0.14	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0	B;B
Vest4		0.18
MutPred		0.18		Loss of solvent accessibility (P = 0.0606);Loss of solvent accessibility (P = 0.0606);
MVP		0.043
MPC		0.024
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.072
gMVP		0.23

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: rs3734354; hg19: chr6-100868779;