7-73593903-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032951.3(MLXIPL):c.2521C>T(p.Arg841Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,614,088 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0070 (48 hom.)
• Consequence: MLXIPL NM_032951.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.58

Genes affected

MLXIPL (HGNC:12744): (MLX interacting protein like) This gene encodes a basic helix-loop-helix leucine zipper transcription factor of the Myc/Max/Mad superfamily. This protein forms a heterodimeric complex and binds and activates, in a glucose-dependent manner, carbohydrate response element (ChoRE) motifs in the promoters of triglyceride synthesis genes. The gene is deleted in Williams-Beuren syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00852406).
• BP6: Variant 7-73593903-G-A is Benign according to our data. Variant chr7-73593903-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 774189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLXIPL	NM_032951.3	c.2521C>T	p.Arg841Trp	missense_variant	17/17	ENST00000313375.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLXIPL	ENST00000313375.8	c.2521C>T	p.Arg841Trp	missense_variant	17/17	1	NM_032951.3	A2

Frequencies

GnomAD3 genomes AF: 0.00507 AC: 771 AN: 152132 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00882

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00514 AC: 1290 AN: 251118 Hom.: 7 AF XY: 0.00523 AC XY: 711 AN XY: 135844

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00924

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00701 AC: 10254 AN: 1461838 Hom.: 48 Cov.: 31 AF XY: 0.00683 AC XY: 4970 AN XY: 727226

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00854

Gnomad4 OTH exome AF: 0.00596

GnomAD4 genome AF: 0.00506 AC: 771 AN: 152250 Hom.: 4 Cov.: 31 AF XY: 0.00470 AC XY: 350 AN XY: 74458

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00882

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00756 Hom.: 8

Bravo AF: 0.00521

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00552 AC: 670

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00763

EpiControl AF: 0.00931

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MLXIPL: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0085	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.047
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		1.0	D;B;B;D
Vest4		0.32
MVP		0.30
MPC		1.8
ClinPred		0.036	T
GERP RS		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs66489924; hg19: chr7-73008233; COSMIC: COSV100515635; COSMIC: COSV100515635;