NM_004970.3:c.1386C>T

Variant names:

• chr16-1791032-G-A
• rs17559
• NM_004970.3:c.1386C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004970.3(IGFALS):​c.1386C>T​(p.Tyr462Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,598,232 control chromosomes in the GnomAD database, including 19,780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4936 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14844 hom.)
• Consequence: IGFALS NM_004970.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.71
• Publications: 28 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-1791032-G-A is Benign according to our data. Variant chr16-1791032-G-A is described in ClinVar as Benign. ClinVar VariationId is 318241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004970.3. 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
	IGFALS	NM_004970.3	MANE Select	c.1386C>T	p.Tyr462Tyr	synonymous	Exon 2 of 2	NP_004961.1	P35858-1
	IGFALS	NM_001146006.2		c.1500C>T	p.Tyr500Tyr	synonymous	Exon 2 of 2	NP_001139478.1	P35858-2
	IGFALS	NR_027389.1		n.1440C>T		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFALS	ENST00000215539.4	TSL:1 MANE Select	c.1386C>T	p.Tyr462Tyr	synonymous	Exon 2 of 2	ENSP00000215539.3	P35858-1
	IGFALS	ENST00000415638.3	TSL:2	c.1500C>T	p.Tyr500Tyr	synonymous	Exon 2 of 2	ENSP00000416683.3	P35858-2
	IGFALS	ENST00000897144.1		c.1461C>T	p.Tyr487Tyr	synonymous	Exon 3 of 3	ENSP00000567203.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30343 AN: 152096 Hom.: 4912 Cov.: 33

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.144 AC: 33667 AN: 233094 AF XY: 0.148

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.0668

Gnomad ASJ exome AF: 0.0887

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.0672

Gnomad NFE exome AF: 0.0940

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.121 AC: 175051 AN: 1446018 Hom.: 14844 Cov.: 33 AF XY: 0.126 AC XY: 90460 AN XY: 719756

African (AFR) AF: 0.457 AC: 15288 AN: 33462

American (AMR) AF: 0.0700 AC: 3129 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0884 AC: 2308 AN: 26114

East Asian (EAS) AF: 0.126 AC: 4987 AN: 39686

South Asian (SAS) AF: 0.310 AC: 26697 AN: 86232

European-Finnish (FIN) AF: 0.0709 AC: 2712 AN: 38226

Middle Eastern (MID) AF: 0.110 AC: 616 AN: 5608

European-Non Finnish (NFE) AF: 0.0999 AC: 111083 AN: 1111748

Other (OTH) AF: 0.137 AC: 8231 AN: 60250

GnomAD4 genome AF: 0.200 AC: 30425 AN: 152214 Hom.: 4936 Cov.: 33 AF XY: 0.198 AC XY: 14699 AN XY: 74414

African (AFR) AF: 0.443 AC: 18379 AN: 41512

American (AMR) AF: 0.103 AC: 1572 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0789 AC: 274 AN: 3472

East Asian (EAS) AF: 0.142 AC: 736 AN: 5166

South Asian (SAS) AF: 0.314 AC: 1515 AN: 4820

European-Finnish (FIN) AF: 0.0685 AC: 728 AN: 10622

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.0994 AC: 6763 AN: 68004

Other (OTH) AF: 0.175 AC: 371 AN: 2114

Alfa AF: 0.126 Hom.: 1178

Bravo AF: 0.207

Asia WGS AF: 0.270 AC: 939 AN: 3478

EpiCase AF: 0.0928

EpiControl AF: 0.0941

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Short stature due to primary acid-labile subunit deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.6
DANN	Benign	0.76
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs17559; hg19: chr16-1841033; COSMIC: COSV51904537; COSMIC: COSV51904537;