4-75950796-A-C

Variant names:

• chr4-75950796-A-C
• rs138382679
• NM_018115.4:c.2018T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018115.4(SDAD1):​c.2018T>G​(p.Leu673Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000342 in 1,581,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SDAD1 NM_018115.4 missense, splice_region
• Scores: Splicing: ADA: 0.003672
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71
• Publications: 3 publications found

Genes affected

SDAD1 (HGNC:25537): (SDA1 domain containing 1) Predicted to be involved in ribosomal large subunit biogenesis and ribosomal large subunit export from nucleus. Predicted to act upstream of or within cellular response to leukemia inhibitory factor. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22375953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDAD1	NM_018115.4	c.2018T>G	p.Leu673Trp	missense_variant, splice_region_variant	Exon 22 of 22	ENST00000356260.10	NP_060585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDAD1	ENST00000356260.10	c.2018T>G	p.Leu673Trp	missense_variant, splice_region_variant	Exon 22 of 22	1	NM_018115.4	ENSP00000348596.5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000309

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000170 AC: 42 AN: 247290 AF XY: 0.000202

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000362 AC: 517 AN: 1429064 Hom.: 0 Cov.: 27 AF XY: 0.000356 AC XY: 252 AN XY: 708826

African (AFR) AF: 0.0000303 AC: 1 AN: 33054

American (AMR) AF: 0.00 AC: 0 AN: 44012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.00 AC: 0 AN: 39308

South Asian (SAS) AF: 0.00 AC: 0 AN: 83434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.000461 AC: 501 AN: 1086898

Other (OTH) AF: 0.000255 AC: 15 AN: 58740

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74456

African (AFR) AF: 0.0000481 AC: 2 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000387 Hom.: 1

Bravo AF: 0.000159

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2018T>G (p.L673W) alteration is located in exon 22 (coding exon 22) of the SDAD1 gene. This alteration results from a T to G substitution at nucleotide position 2018, causing the leucine (L) at amino acid position 673 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.099	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		5.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.99	D;D
Vest4		0.39
MVP		0.55
MPC		0.084
ClinPred		0.21	T
GERP RS		4.0
Varity_R		0.27
gMVP		0.23
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0037
dbscSNV1_RF	Benign	0.054
SpliceAI score (max)		0.090		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: rs138382679; hg19: chr4-76871949;