NM_004970.3:c.210T>A

Variant names:

• chr16-1792208-A-T
• rs3751893
• NM_004970.3:c.210T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004970.3(IGFALS):​c.210T>A​(p.Asp70Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D70D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGFALS NM_004970.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.89
• Publications: 32 publications found

Genes affected

IGFALS (HGNC:5468): (insulin like growth factor binding protein acid labile subunit) The protein encoded by this gene is a serum protein that binds insulin-like growth factors, increasing their half-life and their vascular localization. Production of the encoded protein, which contains twenty leucine-rich repeats, is stimulated by growth hormone. Defects in this gene are a cause of acid-labile subunit deficiency, which maifests itself in a delayed and slow puberty. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SPSB3 (HGNC:30629): (splA/ryanodine receptor domain and SOCS box containing 3) Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be located in cytosol. Predicted to be part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056673676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFALS	NM_004970.3	c.210T>A	p.Asp70Glu	missense_variant	Exon 2 of 2	ENST00000215539.4	NP_004961.1
IGFALS	NM_001146006.2	c.324T>A	p.Asp108Glu	missense_variant	Exon 2 of 2		NP_001139478.1
IGFALS	NR_027389.1	n.264T>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFALS	ENST00000215539.4	c.210T>A	p.Asp70Glu	missense_variant	Exon 2 of 2	1	NM_004970.3	ENSP00000215539.3
IGFALS	ENST00000415638.3	c.324T>A	p.Asp108Glu	missense_variant	Exon 2 of 2	2		ENSP00000416683.3
IGFALS	ENST00000568221.1	c.242T>A	p.Met81Lys	missense_variant	Exon 2 of 2	4		ENSP00000456923.1
SPSB3	ENST00000569769.1	c.-13+1429T>A		intron_variant	Intron 1 of 4	3		ENSP00000455098.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1456760 Hom.: 0 Cov.: 73 AF XY: 0.00 AC XY: 0 AN XY: 724668

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111470

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 98604

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.0010
DANN	Benign	0.54
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.36	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.1	L;.
PhyloP100		-2.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.23	N;N
REVEL	Benign	0.29
Sift	Benign	0.80	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0030	B;.
Vest4		0.012
MutPred		0.26		Gain of helix (P = 0.1736);.;
MVP		0.70
MPC		0.048
ClinPred		0.034	T
GERP RS		-11
Varity_R		0.040
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3751893; hg19: chr16-1842209;