rs568390760

Variant names:

• chr19-10986544-CCCCGGCCCGGGT-C
• rs568390760
• NM_001387283.1:c.722_733delGTCCCGGCCCGG

Your query was ambiguous. Multiple possible variants found:

• chr19-10986544-CCCCGGCCCGGGT-C
• chr19-10986544-CCCCGGCCCGGGT-CCCCGGCCCGGGTCCCGGCCCGGGT

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS1

The NM_003072.5(SMARCA4):​c.722_733delGTCCCGGCCCGG​(p.Gly241_Pro244del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000129 in 1,540,212 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (1 hom.)
• Consequence: SMARCA4 NM_003072.5 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6 O:1
• Conservation: PhyloP100: 6.17
• Publications: 3 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: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003072.5
• BP6: Variant 19-10986544-CCCCGGCCCGGGT-C is Benign according to our data. Variant chr19-10986544-CCCCGGCCCGGGT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000565 (86/152222) while in subpopulation AFR AF = 0.00195 (81/41552). AF 95% confidence interval is 0.00161. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.722_733delGTCCCGGCCCGG	p.Gly241_Pro244del	disruptive_inframe_deletion	Exon 4 of 36	NP_001374212.1	Q9HBD4
	SMARCA4	NM_003072.5	MANE Select	c.722_733delGTCCCGGCCCGG	p.Gly241_Pro244del	disruptive_inframe_deletion	Exon 4 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.722_733delGTCCCGGCCCGG	p.Gly241_Pro244del	disruptive_inframe_deletion	Exon 4 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.722_733delGTCCCGGCCCGG	p.Gly241_Pro244del	disruptive_inframe_deletion	Exon 4 of 36	ENSP00000495368.1	Q9HBD4
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.722_733delGTCCCGGCCCGG	p.Gly241_Pro244del	disruptive_inframe_deletion	Exon 4 of 35	ENSP00000343896.4	P51532-1
	SMARCA4	ENST00000643549.1		c.722_733delGTCCCGGCCCGG	p.Gly241_Pro244del	disruptive_inframe_deletion	Exon 4 of 35	ENSP00000493975.1	A0A2R8Y4P4

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 14 AN: 134992 AF XY: 0.0000542

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000488

GnomAD4 exome AF: 0.0000814 AC: 113 AN: 1387990 Hom.: 1 AF XY: 0.0000657 AC XY: 45 AN XY: 684998

African (AFR) AF: 0.00212 AC: 67 AN: 31572

American (AMR) AF: 0.000168 AC: 6 AN: 35656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.0000840 AC: 3 AN: 35726

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38756

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5690

European-Non Finnish (NFE) AF: 0.0000167 AC: 18 AN: 1078468

Other (OTH) AF: 0.000242 AC: 14 AN: 57896

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74412

African (AFR) AF: 0.00195 AC: 81 AN: 41552

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

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

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.000650

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	not specified (2)
-	-	1	Rhabdoid tumor predisposition syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2
Mutation Taster		=151/49	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs568390760;

hg19: chr19-11097220;