16-1792208-A-G

Variant names:

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

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.210T>C​(p.Asp70Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,608,936 control chromosomes in the GnomAD database, including 526,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49797 hom., cov: 35)
  • Exomes 𝑓: 0.81 (476598 hom.)
• Consequence: IGFALS NM_004970.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0638804E-7).
• BP6: Variant 16-1792208-A-G is Benign according to our data. Variant chr16-1792208-A-G is described in ClinVar as Benign. ClinVar VariationId is 318265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.821 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.210T>C	p.Asp70Asp	synonymous	Exon 2 of 2	NP_004961.1	P35858-1
	IGFALS	NM_001146006.2		c.324T>C	p.Asp108Asp	synonymous	Exon 2 of 2	NP_001139478.1	P35858-2
	IGFALS	NR_027389.1		n.264T>C		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.210T>C	p.Asp70Asp	synonymous	Exon 2 of 2	ENSP00000215539.3	P35858-1
	IGFALS	ENST00000568221.1	TSL:4	c.242T>C	p.Met81Thr	missense	Exon 2 of 2	ENSP00000456923.1	H3BSX8
	IGFALS	ENST00000415638.3	TSL:2	c.324T>C	p.Asp108Asp	synonymous	Exon 2 of 2	ENSP00000416683.3	P35858-2

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122827 AN: 152142 Hom.: 49752 Cov.: 35

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.850

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.828

GnomAD2 exomes AF: 0.798 AC: 188802 AN: 236560 AF XY: 0.795

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.817

Gnomad ASJ exome AF: 0.850

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.820

Gnomad OTH exome AF: 0.802

GnomAD4 exome AF: 0.808 AC: 1177070 AN: 1456676 Hom.: 476598 Cov.: 73 AF XY: 0.806 AC XY: 583762 AN XY: 724614

African (AFR) AF: 0.833 AC: 27868 AN: 33460

American (AMR) AF: 0.811 AC: 36116 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.847 AC: 22092 AN: 26070

East Asian (EAS) AF: 0.693 AC: 27475 AN: 39636

South Asian (SAS) AF: 0.749 AC: 64541 AN: 86146

European-Finnish (FIN) AF: 0.721 AC: 35568 AN: 49332

Middle Eastern (MID) AF: 0.847 AC: 4882 AN: 5764

European-Non Finnish (NFE) AF: 0.819 AC: 910098 AN: 1111444

Other (OTH) AF: 0.803 AC: 48430 AN: 60276

GnomAD4 genome AF: 0.807 AC: 122932 AN: 152260 Hom.: 49797 Cov.: 35 AF XY: 0.799 AC XY: 59482 AN XY: 74428

African (AFR) AF: 0.829 AC: 34438 AN: 41562

American (AMR) AF: 0.807 AC: 12350 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 2950 AN: 3472

East Asian (EAS) AF: 0.723 AC: 3736 AN: 5168

South Asian (SAS) AF: 0.763 AC: 3685 AN: 4832

European-Finnish (FIN) AF: 0.707 AC: 7496 AN: 10598

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55459 AN: 68014

Other (OTH) AF: 0.829 AC: 1750 AN: 2112

Alfa AF: 0.817 Hom.: 98604

Bravo AF: 0.820

TwinsUK AF: 0.816 AC: 3024

ALSPAC AF: 0.814 AC: 3139

ESP6500AA AF: 0.816 AC: 3580

ESP6500EA AF: 0.822 AC: 7065

ExAC AF: 0.796 AC: 95593

Asia WGS AF: 0.723 AC: 2516 AN: 3478

EpiCase AF: 0.823

EpiControl AF: 0.827

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.97	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.015
DANN	Benign	0.27
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	9.1e-7	T
PhyloP100		-2.9
PROVEAN	Pathogenic	-6.0	D
Vest4		0.066
GERP RS		-11
Mutation Taster		=97/3	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: rs3751893; hg19: chr16-1842209; COSMIC: COSV51904911; COSMIC: COSV51904911;