5-154455960-A-T

Variant names:

• chr5-154455960-A-T
• rs916419432
• NM_024632.6:c.484A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024632.6(SAP30L):​c.484A>T​(p.Ile162Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I162V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SAP30L NM_024632.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.11
• Publications: 0 publications found

Genes affected

SAP30L (HGNC:25663): (SAP30 like) Enables several functions, including non-sequence-specific DNA binding activity, bending; phosphatidylinositol phosphate binding activity; and zinc ion binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in fibrillar center and nucleoplasm. Part of histone deacetylase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024632.6. 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
	SAP30L	NM_024632.6	MANE Select	c.484A>T	p.Ile162Phe	missense	Exon 4 of 4	NP_078908.1	Q9HAJ7-1
	SAP30L	NM_001131062.2		c.361A>T	p.Ile121Phe	missense	Exon 3 of 3	NP_001124534.1	Q9HAJ7-3
	SAP30L	NM_001131063.2		c.346A>T	p.Ile116Phe	missense	Exon 3 of 3	NP_001124535.1	Q9HAJ7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAP30L	ENST00000297109.11	TSL:1 MANE Select	c.484A>T	p.Ile162Phe	missense	Exon 4 of 4	ENSP00000297109.5	Q9HAJ7-1
	SAP30L	ENST00000517926.1	TSL:1	n.484A>T		non_coding_transcript_exon	Exon 2 of 2
	SAP30L	ENST00000937072.1		c.553A>T	p.Ile185Phe	missense	Exon 5 of 5	ENSP00000607131.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ 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 Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.74	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.44		Loss of MoRF binding (P = 0.0971)
MVP		0.36
MPC		1.9
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.79
gMVP		0.72
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs916419432; hg19: chr5-153835520;