19-10961163-C-T

Variant names:

• chr19-10961163-C-T
• rs574982898
• NM_001387283.1:c.-40C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003072.5(SMARCA4):​c.-43C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 147,894 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA4 NM_003072.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.935
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-10961163-C-T is Benign according to our data. Variant chr19-10961163-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00272 (402/147894) while in subpopulation NFE AF = 0.00356 (236/66364). AF 95% confidence interval is 0.00318. There are 2 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.-43C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 35	ENST00000344626.10	NP_003063.2
SMARCA4	NM_001387283.1	c.-40C>T		5_prime_UTR_variant	Exon 1 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.-43C>T		5_prime_UTR_variant	Exon 1 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.-43C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.-203C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.-43C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.-272C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000646693.2	c.-40C>T		5_prime_UTR_variant	Exon 1 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.-43C>T		5_prime_UTR_variant	Exon 1 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.-40C>T		5_prime_UTR_variant	Exon 1 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.-203C>T		5_prime_UTR_variant	Exon 1 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.-43C>T		5_prime_UTR_variant	Exon 1 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.-40C>T		5_prime_UTR_variant	Exon 1 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.-272C>T		5_prime_UTR_variant	Exon 1 of 35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 402 AN: 147786 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000764

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000212

Gnomad MID AF: 0.0105

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00394

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 30 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 24

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 20

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.00272 AC: 402 AN: 147894 Hom.: 2 Cov.: 31 AF XY: 0.00251 AC XY: 181 AN XY: 72168

African (AFR) AF: 0.000761 AC: 31 AN: 40716

American (AMR) AF: 0.00340 AC: 51 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 70 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5004

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4774

European-Finnish (FIN) AF: 0.000212 AC: 2 AN: 9414

Middle Eastern (MID) AF: 0.0112 AC: 3 AN: 268

European-Non Finnish (NFE) AF: 0.00356 AC: 236 AN: 66364

Other (OTH) AF: 0.00389 AC: 8 AN: 2056

Alfa AF: 0.00313 Hom.: 0

Bravo AF: 0.00281

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Mar 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Coffin-Siris syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.98
PhyloP100		0.94
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=299/1	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: rs574982898; hg19: chr19-11071839; COSMIC: COSV107432118;