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GeneBe

16-51137251-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_002968.3(SALL1):c.3836C>T(p.Thr1279Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 152084 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SALL1
NM_002968.3 missense

Scores

3
7
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.17

Links

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
?
Computational evidence support a benign effect (MetaRNN=0.2836892).
BS1
?
Variant frequency is greater than expected. gnomad allele frequency = 0.0000329 (5/152084) while in subpopulation NFE AF= 0.0000588 (4/68018). AF 95% confidence interval is 0.0000197. There are 0 homozygotes in gnomad. There are 2 alleles in male gnomad subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SALL1NM_002968.3 linkuse as main transcriptc.3836C>T p.Thr1279Met missense_variant 3/3 ENST00000251020.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SALL1ENST00000251020.9 linkuse as main transcriptc.3836C>T p.Thr1279Met missense_variant 3/31 NM_002968.3 P2Q9NSC2-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152084
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251474
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000287
AC:
42
AN:
1461870
Hom.:
2
AF XY:
0.0000344
AC XY:
25
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.0000662
Alfa
AF:
0.0000900
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000494
AC:
6
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Townes syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMar 04, 2022This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1279 of the SALL1 protein (p.Thr1279Met). This variant is present in population databases (rs776104367, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SALL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 829915). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2021The c.3836C>T (p.T1279M) alteration is located in exon 3 (coding exon 3) of the SALL1 gene. This alteration results from a C to T substitution at nucleotide position 3836, causing the threonine (T) at amino acid position 1279 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 15, 2021In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Townes-Brocks syndrome 1 Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic HealthcareOct 24, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.042
T
BayesDel_noAF
Uncertain
0.0
Cadd
Uncertain
26
Dann
Uncertain
1.0
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-0.60
T
MutationTaster
Benign
1.0
D;D;D;D
PROVEAN
Uncertain
-2.5
D;N
REVEL
Benign
0.28
Sift
Uncertain
0.016
D;D
Sift4G
Uncertain
0.0080
D;D
Polyphen
1.0
.;D
Vest4
0.47
MutPred
0.27
.;Loss of relative solvent accessibility (P = 0.0071);
MVP
0.44
MPC
0.77
ClinPred
0.33
T
GERP RS
5.8
Varity_R
0.13
gMVP
0.61

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776104367; hg19: chr16-51171162; COSMIC: COSV51762582; COSMIC: COSV51762582; API