12-50085546-G-C

Variant names:

• chr12-50085546-G-C
• rs1422306360
• NM_003076.5:c.177G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003076.5(SMARCD1):​c.177G>C​(p.Pro59Pro) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000243 in 1,233,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P59P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: SMARCD1 NM_003076.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.23
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.177G>C	p.Pro59Pro	splice_region synonymous	Exon 1 of 13	NP_003067.3
	SMARCD1	NM_139071.3		c.177G>C	p.Pro59Pro	splice_region synonymous	Exon 1 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.177G>C	p.Pro59Pro	splice_region synonymous	Exon 1 of 13	ENSP00000378414.4	Q96GM5-1
	SMARCD1	ENST00000381513.8	TSL:1	c.177G>C	p.Pro59Pro	splice_region synonymous	Exon 1 of 12	ENSP00000370924.4	Q96GM5-2
	SMARCD1	ENST00000547247.5	TSL:1	n.205G>C		splice_region non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151640 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1081496 Hom.: 0 Cov.: 32 AF XY: 0.00000391 AC XY: 2 AN XY: 510912

African (AFR) AF: 0.00 AC: 0 AN: 22950

American (AMR) AF: 0.00 AC: 0 AN: 8538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14366

East Asian (EAS) AF: 0.00 AC: 0 AN: 26536

South Asian (SAS) AF: 0.00 AC: 0 AN: 19542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2926

European-Non Finnish (NFE) AF: 0.00000217 AC: 2 AN: 920034

Other (OTH) AF: 0.00 AC: 0 AN: 43674

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151640 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74040

African (AFR) AF: 0.00 AC: 0 AN: 41286

American (AMR) AF: 0.0000656 AC: 1 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67834

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.94
PhyloP100		4.2
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
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: rs1422306360; hg19: chr12-50479329;