chr12-50086282-G-T

Variant names:

• chr12-50086282-G-T
• NM_003076.5:c.299G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003076.5(SMARCD1):​c.299G>T​(p.Arg100Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SMARCD1 NM_003076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99
• Publications: 0 publications found

Genes affected

SMARCD1 (HGNC:11106): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 1) The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI and has sequence similarity to the yeast Swp73 protein. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SMARCD1 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• Coffin-Siris syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003076.5. 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
	SMARCD1	NM_003076.5	MANE Select	c.299G>T	p.Arg100Leu	missense	Exon 2 of 13	NP_003067.3
	SMARCD1	NM_139071.3		c.299G>T	p.Arg100Leu	missense	Exon 2 of 12	NP_620710.2	Q96GM5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCD1	ENST00000394963.9	TSL:1 MANE Select	c.299G>T	p.Arg100Leu	missense	Exon 2 of 13	ENSP00000378414.4	Q96GM5-1
	SMARCD1	ENST00000381513.8	TSL:1	c.299G>T	p.Arg100Leu	missense	Exon 2 of 12	ENSP00000370924.4	Q96GM5-2
	SMARCD1	ENST00000547247.5	TSL:1	n.327G>T		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.036
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.51
Sift	Benign	0.061	T
Sift4G	Benign	0.16	T
Polyphen		0.67	P
Vest4		0.75
MutPred		0.36		Loss of MoRF binding (P = 0.0524)
MVP		0.61
MPC		1.3
ClinPred		0.95	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.21
gMVP		0.82
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

hg19: chr12-50480065;