rs9441940

Positions:

• chr1-223005136-G-A
• chr1-223005136-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377229.1(DISP1):​c.3739G>A​(p.Ala1247Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,614,050 control chromosomes in the GnomAD database, including 22,294 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1247S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1471 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20823 hom.)
• Consequence: DISP1 NM_001377229.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.77

Genes affected

DISP1 (HGNC:19711): (dispatched RND transporter family member 1) The pattern of cellular proliferation and differentiation that leads to normal development of embryonic structures often depends upon the localized production of secreted protein signals. Cells surrounding the source of a particular signal respond in a graded manner according to the effective concentration of the signal, and this response produces the pattern of cell types constituting the mature structure. A novel segment-polarity gene known as dispatched has been identified in Drosophila and its protein product is required for normal Hedgehog (Hh) signaling. This gene is one of two human homologs of Drosophila dispatched and, based on sequence identity to its mouse counterpart, the encoded protein may play an essential role in Hh patterning activities in the early embryo. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.4002147E-4).
• BP6: Variant 1-223005136-G-A is Benign according to our data. Variant chr1-223005136-G-A is described in ClinVar as [Benign]. Clinvar id is 811581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISP1	NM_001377229.1	c.3739G>A	p.Ala1247Thr	missense_variant	9/9	ENST00000675850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISP1	ENST00000675850.1	c.3739G>A	p.Ala1247Thr	missense_variant	9/9		NM_001377229.1	P1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18628 AN: 152068 Hom.: 1471 Cov.: 32

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0882

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.127 AC: 31847 AN: 251056 Hom.: 2501 AF XY: 0.131 AC XY: 17718 AN XY: 135660

Gnomad AFR exome AF: 0.0381

Gnomad AMR exome AF: 0.0758

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0951

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.162 AC: 237406 AN: 1461864 Hom.: 20823 Cov.: 68 AF XY: 0.161 AC XY: 116975 AN XY: 727228

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.0780

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0977

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.122 AC: 18620 AN: 152186 Hom.: 1471 Cov.: 32 AF XY: 0.119 AC XY: 8823 AN XY: 74410

Gnomad4 AFR AF: 0.0397

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.146

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.0886

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.115

Alfa AF: 0.156 Hom.: 2812

Bravo AF: 0.114

TwinsUK AF: 0.173 AC: 643

ALSPAC AF: 0.171 AC: 659

ESP6500AA AF: 0.0468 AC: 206

ESP6500EA AF: 0.182 AC: 1567

ExAC AF: 0.126 AC: 15335

EpiCase AF: 0.178

EpiControl AF: 0.171

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.0010
DANN	Benign	0.52
DEOGEN2	Benign	0.027	T
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.00074	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.90	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.47	N
REVEL	Uncertain	0.30
Sift	Benign	0.51	T
Sift4G	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.17
ClinPred		0.0073	T
GERP RS		-11
Varity_R		0.022
gMVP		0.22

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: rs9441940; hg19: chr1-223178478; COSMIC: COSV52656020;