16-51141744-CGCTGCTGCTGCTGCTGCT-CGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr16-51141744-C-CGCTGCT
• rs113614842
• NM_002968.3:c.472_477dupAGCAGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_002968.3(SALL1):​c.472_477dupAGCAGC​(p.Ser158_Ser159dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,579,948 control chromosomes in the GnomAD database, including 38 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0098 (31 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (7 hom.)
• Consequence: SALL1 NM_002968.3 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.34
• Publications: 2 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002968.3
• BP6: Variant 16-51141744-C-CGCTGCT is Benign according to our data. Variant chr16-51141744-C-CGCTGCT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 319615.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00979 (1479/151100) while in subpopulation AFR AF = 0.0334 (1372/41132). AF 95% confidence interval is 0.0319. There are 31 homozygotes in GnomAd4. There are 735 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1479 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.472_477dupAGCAGC	p.Ser158_Ser159dup	conservative_inframe_insertion	Exon 2 of 3	NP_002959.2	Q9NSC2-1
	SALL1	NM_001127892.2		c.181_186dupAGCAGC	p.Ser61_Ser62dup	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.472_477dupAGCAGC	p.Ser158_Ser159dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000251020.4	Q9NSC2-1
	SALL1	ENST00000566102.1	TSL:1	c.77-4198_77-4193dupAGCAGC		intron	N/A	ENSP00000455582.1	H3BQ32
	SALL1	ENST00000440970.6	TSL:5	c.472_477dupAGCAGC	p.Ser158_Ser159dup	conservative_inframe_insertion	Exon 3 of 4	ENSP00000407914.2	Q9NSC2-1

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1476 AN: 150990 Hom.: 31 Cov.: 31

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00408

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000780

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.000478

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00625

GnomAD2 exomes AF: 0.00288 AC: 615 AN: 213596 AF XY: 0.00222

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.000646

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00124 AC: 1766 AN: 1428848 Hom.: 7 Cov.: 43 AF XY: 0.00106 AC XY: 755 AN XY: 710654

African (AFR) AF: 0.0341 AC: 1115 AN: 32694

American (AMR) AF: 0.00214 AC: 93 AN: 43538

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

East Asian (EAS) AF: 0.00278 AC: 107 AN: 38532

South Asian (SAS) AF: 0.00167 AC: 140 AN: 83934

European-Finnish (FIN) AF: 0.000443 AC: 23 AN: 51878

Middle Eastern (MID) AF: 0.00165 AC: 9 AN: 5448

European-Non Finnish (NFE) AF: 0.000128 AC: 139 AN: 1088548

Other (OTH) AF: 0.00238 AC: 140 AN: 58812

GnomAD4 genome AF: 0.00979 AC: 1479 AN: 151100 Hom.: 31 Cov.: 31 AF XY: 0.00996 AC XY: 735 AN XY: 73818

African (AFR) AF: 0.0334 AC: 1372 AN: 41132

American (AMR) AF: 0.00407 AC: 62 AN: 15218

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

East Asian (EAS) AF: 0.000782 AC: 4 AN: 5116

South Asian (SAS) AF: 0.00106 AC: 5 AN: 4736

European-Finnish (FIN) AF: 0.000478 AC: 5 AN: 10452

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000236 AC: 16 AN: 67696

Other (OTH) AF: 0.00618 AC: 13 AN: 2102

Alfa AF: 0.000153 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Townes syndrome (1)
-	1	-	Townes-Brocks syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=81/19	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs113614842; hg19: chr16-51175655; COSMIC: COSV104566676; COSMIC: COSV104566676;