rs3812316

Variant names:

• chr7-73606007-C-G
• rs3812316
• NM_032951.3:c.723G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032951.3(MLXIPL):​c.723G>C​(p.Gln241His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,585,936 control chromosomes in the GnomAD database, including 11,463 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.095 (810 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10653 hom.)
• Consequence: MLXIPL NM_032951.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 115 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015729964).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLXIPL	NM_032951.3	c.723G>C	p.Gln241His	missense_variant	Exon 6 of 17	ENST00000313375.8	NP_116569.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLXIPL	ENST00000313375.8	c.723G>C	p.Gln241His	missense_variant	Exon 6 of 17	1	NM_032951.3	ENSP00000320886.3

Frequencies

GnomAD3 genomes AF: 0.0946 AC: 14400 AN: 152206 Hom.: 809 Cov.: 33

Gnomad AFR AF: 0.0438

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0925

Gnomad SAS AF: 0.0879

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.0869

GnomAD2 exomes AF: 0.101 AC: 20140 AN: 200060 AF XY: 0.102

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.0621

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.0863

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.119 AC: 169931 AN: 1433610 Hom.: 10653 Cov.: 37 AF XY: 0.118 AC XY: 83866 AN XY: 710372

African (AFR) AF: 0.0419 AC: 1388 AN: 33122

American (AMR) AF: 0.0615 AC: 2466 AN: 40120

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2882 AN: 25482

East Asian (EAS) AF: 0.0914 AC: 3533 AN: 38642

South Asian (SAS) AF: 0.0906 AC: 7447 AN: 82190

European-Finnish (FIN) AF: 0.126 AC: 6490 AN: 51312

Middle Eastern (MID) AF: 0.153 AC: 876 AN: 5726

European-Non Finnish (NFE) AF: 0.126 AC: 138301 AN: 1097738

Other (OTH) AF: 0.110 AC: 6548 AN: 59278

GnomAD4 genome AF: 0.0946 AC: 14408 AN: 152326 Hom.: 810 Cov.: 33 AF XY: 0.0942 AC XY: 7017 AN XY: 74480

African (AFR) AF: 0.0436 AC: 1815 AN: 41592

American (AMR) AF: 0.0709 AC: 1084 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3468

East Asian (EAS) AF: 0.0929 AC: 481 AN: 5176

South Asian (SAS) AF: 0.0882 AC: 426 AN: 4832

European-Finnish (FIN) AF: 0.119 AC: 1267 AN: 10624

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.127 AC: 8639 AN: 68022

Other (OTH) AF: 0.0912 AC: 193 AN: 2116

Alfa AF: 0.118 Hom.: 849

Bravo AF: 0.0863

TwinsUK AF: 0.123 AC: 455

ALSPAC AF: 0.135 AC: 521

ESP6500AA AF: 0.0447 AC: 197

ESP6500EA AF: 0.119 AC: 1027

ExAC AF: 0.0863 AC: 10397

Asia WGS AF: 0.102 AC: 353 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.097	.;.;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.63	T;T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;L;.
PhyloP100		1.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.17	T;T;T;T;D
Sift4G	Benign	0.58	T;T;T;T;.
Polyphen		0.039	B;B;B;B;.
Vest4		0.13
MutPred		0.74		Loss of catalytic residue at Q241 (P = 0.0278);Loss of catalytic residue at Q241 (P = 0.0278);Loss of catalytic residue at Q241 (P = 0.0278);Loss of catalytic residue at Q241 (P = 0.0278);.;
MPC		0.41
ClinPred		0.020	T
GERP RS		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.28
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: rs3812316; hg19: chr7-73020337; COSMIC: COSV57666523; COSMIC: COSV57666523;