16-51141744-C-CGCCGCTGCT

Variant names:

• chr16-51141744-C-CGCCGCTGCT
• rs1555475415
• NM_002968.3:c.477_478insAGCAGCGGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_002968.3(SALL1):​c.477_478insAGCAGCGGC​(p.Ser159_Gly160insSerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 1,580,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SALL1 NM_002968.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.34
• Publications: 0 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002968.3
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000529 (8/151110) while in subpopulation SAS AF = 0.000211 (1/4736). AF 95% confidence interval is 0.0000794. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 8 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.477_478insAGCAGCGGC	p.Ser159_Gly160insSerSerGly	conservative_inframe_insertion	Exon 2 of 3	NP_002959.2	Q9NSC2-1
	SALL1	NM_001127892.2		c.186_187insAGCAGCGGC	p.Ser62_Gly63insSerSerGly	conservative_inframe_insertion	Exon 2 of 3	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.477_478insAGCAGCGGC	p.Ser159_Gly160insSerSerGly	conservative_inframe_insertion	Exon 2 of 3	ENSP00000251020.4	Q9NSC2-1
	SALL1	ENST00000566102.1	TSL:1	c.77-4193_77-4192insAGCAGCGGC		intron	N/A	ENSP00000455582.1	H3BQ32
	SALL1	ENST00000440970.6	TSL:5	c.477_478insAGCAGCGGC	p.Ser159_Gly160insSerSerGly	conservative_inframe_insertion	Exon 3 of 4	ENSP00000407914.2	Q9NSC2-1

Frequencies

GnomAD3 genomes AF: 0.0000530 AC: 8 AN: 151000 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 26 AN: 1428924 Hom.: 0 Cov.: 43 AF XY: 0.0000211 AC XY: 15 AN XY: 710698

African (AFR) AF: 0.000153 AC: 5 AN: 32712

American (AMR) AF: 0.0000230 AC: 1 AN: 43538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25464

East Asian (EAS) AF: 0.00 AC: 0 AN: 38532

South Asian (SAS) AF: 0.000143 AC: 12 AN: 83984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51878

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5450

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1088550

Other (OTH) AF: 0.0000340 AC: 2 AN: 58816

GnomAD4 genome AF: 0.0000529 AC: 8 AN: 151110 Hom.: 0 Cov.: 31 AF XY: 0.0000542 AC XY: 4 AN XY: 73820

African (AFR) AF: 0.000170 AC: 7 AN: 41142

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10452

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67696

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Townes-Brocks syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=78/22	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1555475415; hg19: chr16-51175655;