16-51141744-C-CGCCGCTGCTGCT

Variant names:

• chr16-51141744-C-CGCCGCTGCTGCT
• rs1555475415
• NM_002968.3:c.477_478insAGCAGCAGCGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_002968.3(SALL1):​c.477_478insAGCAGCAGCGGC​(p.Ser159_Gly160insSerSerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,428,926 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SALL1 NM_002968.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Townes-Brocks syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002968.3

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL1	NM_002968.3	MANE Select	c.477_478insAGCAGCAGCGGC	p.Ser159_Gly160insSerSerSerGly	conservative_inframe_insertion	Exon 2 of 3	NP_002959.2
	SALL1	NM_001127892.2		c.186_187insAGCAGCAGCGGC	p.Ser62_Gly63insSerSerSerGly	conservative_inframe_insertion	Exon 2 of 3	NP_001121364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL1	ENST00000251020.9	TSL:1 MANE Select	c.477_478insAGCAGCAGCGGC	p.Ser159_Gly160insSerSerSerGly	conservative_inframe_insertion	Exon 2 of 3	ENSP00000251020.4
	SALL1	ENST00000566102.1	TSL:1	c.77-4193_77-4192insAGCAGCAGCGGC		intron	N/A	ENSP00000455582.1
	SALL1	ENST00000440970.6	TSL:5	c.477_478insAGCAGCAGCGGC	p.Ser159_Gly160insSerSerSerGly	conservative_inframe_insertion	Exon 3 of 4	ENSP00000407914.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1428926 Hom.: 0 Cov.: 43 AF XY: 0.00000563 AC XY: 4 AN XY: 710698

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

African (AFR) AF: 0.0000306 AC: 1 AN: 32714

American (AMR) AF: 0.00 AC: 0 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: 0.0000238 AC: 2 AN: 83984

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1088550

Other (OTH) AF: 0.00 AC: 0 AN: 58816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000016091), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (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;