1-222943130-G-A

Position:

• chr1-222943130-G-A

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.307G>A​(p.Glu103Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,312 control chromosomes in the GnomAD database, including 21,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E103D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2054 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19654 hom.)
• Consequence: DISP1 NM_001377229.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.87

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=0.0034455955).
• BP6: Variant 1-222943130-G-A is Benign according to our data. Variant chr1-222943130-G-A is described in ClinVar as [Benign]. Clinvar id is 262129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISP1	NM_001377229.1	c.307G>A	p.Glu103Lys	missense_variant	3/9	ENST00000675850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISP1	ENST00000675850.1	c.307G>A	p.Glu103Lys	missense_variant	3/9		NM_001377229.1	P1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24674 AN: 151926 Hom.: 2042 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.179 AC: 45021 AN: 251192 Hom.: 4534 AF XY: 0.182 AC XY: 24753 AN XY: 135726

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.298

Gnomad SAS exome AF: 0.284

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.156 AC: 228147 AN: 1461268 Hom.: 19654 Cov.: 33 AF XY: 0.159 AC XY: 115902 AN XY: 726796

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.316

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.163 AC: 24708 AN: 152044 Hom.: 2054 Cov.: 32 AF XY: 0.168 AC XY: 12479 AN XY: 74322

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.166

Alfa AF: 0.142 Hom.: 3816

Bravo AF: 0.161

TwinsUK AF: 0.149 AC: 553

ALSPAC AF: 0.134 AC: 516

ESP6500AA AF: 0.167 AC: 738

ESP6500EA AF: 0.137 AC: 1176

ExAC AF: 0.178 AC: 21672

Asia WGS AF: 0.287 AC: 994 AN: 3478

EpiCase AF: 0.142

EpiControl AF: 0.140

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
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	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.097
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.99	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.14
Sift	Benign	0.75	T
Sift4G	Benign	0.51	T
Polyphen		0.23	B
Vest4		0.11
MPC		0.22
ClinPred		0.0084	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.24

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: rs2609383; hg19: chr1-223116472; COSMIC: COSV52654796; COSMIC: COSV52654796;