19-11060123-C-T

Variant names:

• chr19-11060123-C-T
• rs878854234
• NM_001387283.1:c.4943C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS1

The NM_003072.5(SMARCA4):​c.4847C>T​(p.Pro1616Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,550,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1616S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 1.52
• Publications: 4 publications found

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and 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, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• otosclerosis

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30671942).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000394 (6/152210) while in subpopulation NFE AF = 0.0000882 (6/68038). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003072.5. 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
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.4943C>T	p.Pro1648Leu	missense	Exon 35 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.4847C>T	p.Pro1616Leu	missense	Exon 34 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.4943C>T	p.Pro1648Leu	missense	Exon 35 of 36	NP_001122321.1	Q9HBD4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.4943C>T	p.Pro1648Leu	missense	Exon 35 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.4847C>T	p.Pro1616Leu	missense	Exon 34 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.4853C>T	p.Pro1618Leu	missense	Exon 34 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000196 AC: 3 AN: 153050 AF XY: 0.0000247

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000513

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 31 AN: 1398608 Hom.: 0 Cov.: 33 AF XY: 0.0000217 AC XY: 15 AN XY: 689868

African (AFR) AF: 0.0000633 AC: 2 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.0000222 AC: 24 AN: 1078904

Other (OTH) AF: 0.0000690 AC: 4 AN: 57980

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Rhabdoid tumor predisposition syndrome 2 (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Intellectual disability, autosomal dominant 16 (1)
-	1	-	not provided (1)
-	-	1	SMARCA4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.068	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.17	T
Polyphen		0.84	P
Vest4		0.24
MVP		0.64
MPC		1.1
ClinPred		0.55	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.091
gMVP		0.62
Mutation Taster		=90/10	polymorphism

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: rs878854234; hg19: chr19-11170799; COSMIC: COSV105909522;