16-51137582-CAGAG-CAGAGAG

Variant names:

• chr16-51137582-C-CAG
• rs142249003
• NM_002968.3:c.3535-32_3535-31dupCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002968.3(SALL1):​c.3535-32_3535-31dupCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000652 in 1,503,168 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: SALL1 NM_002968.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.256
• Publications: 1 publications found

Genes affected

SALL1 (HGNC:10524): (spalt like transcription factor 1) The protein encoded by this gene is a zinc finger transcriptional repressor and may be part of the NuRD histone deacetylase complex (HDAC). Defects in this gene are a cause of Townes-Brocks syndrome (TBS) as well as bronchio-oto-renal syndrome (BOR). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SALL1 Gene-Disease associations (from GenCC):

• Townes-Brocks syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• Townes-Brocks syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000864 (13/150440) while in subpopulation AMR AF = 0.000132 (2/15104). AF 95% confidence interval is 0.0000327. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002968.3. 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
	SALL1	NM_002968.3	MANE Select	c.3535-32_3535-31dupCT		intron	N/A	NP_002959.2	Q9NSC2-1
	SALL1	NM_001127892.2		c.3244-32_3244-31dupCT		intron	N/A	NP_001121364.1	Q9NSC2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL1	ENST00000251020.9	TSL:1 MANE Select	c.3535-31_3535-30insCT		intron	N/A	ENSP00000251020.4	Q9NSC2-1
	SALL1	ENST00000566102.1	TSL:1	c.77-31_77-30insCT		intron	N/A	ENSP00000455582.1	H3BQ32
	SALL1	ENST00000440970.6	TSL:5	c.3535-31_3535-30insCT		intron	N/A	ENSP00000407914.2	Q9NSC2-1

Frequencies

GnomAD3 genomes AF: 0.0000798 AC: 12 AN: 150332 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000985

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000740

Gnomad OTH AF: 0.000487

GnomAD2 exomes AF: 0.000179 AC: 28 AN: 156212 AF XY: 0.000164

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.000280

Gnomad OTH exome AF: 0.000263

GnomAD4 exome AF: 0.0000628 AC: 85 AN: 1352728 Hom.: 0 Cov.: 17 AF XY: 0.0000650 AC XY: 44 AN XY: 676818

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000639 AC: 2 AN: 31298

American (AMR) AF: 0.0000917 AC: 4 AN: 43626

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25072

East Asian (EAS) AF: 0.0000780 AC: 3 AN: 38456

South Asian (SAS) AF: 0.0000363 AC: 3 AN: 82668

European-Finnish (FIN) AF: 0.000143 AC: 7 AN: 48912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.0000588 AC: 60 AN: 1020664

Other (OTH) AF: 0.0000885 AC: 5 AN: 56502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000864 AC: 13 AN: 150440 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 8 AN XY: 73454

African (AFR) AF: 0.0000975 AC: 4 AN: 41044

American (AMR) AF: 0.000132 AC: 2 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.0000985 AC: 1 AN: 10150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000740 AC: 5 AN: 67570

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

Alfa AF: 0.00 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs142249003; hg19: chr16-51171493;