rs2609383

Variant names:

• chr1-222943130-G-A
• rs2609383
• NM_001377229.1:c.307G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-222943130-G-A
• chr1-222943130-G-C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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. 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:5
• Conservation: PhyloP100: 1.87
• Publications: 24 publications found

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]

DISP1 Gene-Disease associations (from GenCC):

• holoprosencephaly

  Inheritance: AR, AD, SD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Illumina

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377229.1. 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
	DISP1	NM_001377229.1	MANE Select	c.307G>A	p.Glu103Lys	missense	Exon 3 of 9	NP_001364158.1
	DISP1	NM_001369594.1		c.307G>A	p.Glu103Lys	missense	Exon 2 of 8	NP_001356523.1
	DISP1	NM_001377228.1		c.307G>A	p.Glu103Lys	missense	Exon 2 of 8	NP_001364157.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISP1	ENST00000675850.1	MANE Select	c.307G>A	p.Glu103Lys	missense	Exon 3 of 9	ENSP00000502357.1
	DISP1	ENST00000284476.7	TSL:1	c.307G>A	p.Glu103Lys	missense	Exon 2 of 8	ENSP00000284476.6
	DISP1	ENST00000482856.1	TSL:1	n.454G>A		non_coding_transcript_exon	Exon 2 of 2

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

GnomAD2 exomes AF: 0.179 AC: 45021 AN: 251192 AF XY: 0.182

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 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

African (AFR) AF: 0.164 AC: 5495 AN: 33470

American (AMR) AF: 0.198 AC: 8854 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3402 AN: 26130

East Asian (EAS) AF: 0.316 AC: 12542 AN: 39678

South Asian (SAS) AF: 0.277 AC: 23929 AN: 86250

European-Finnish (FIN) AF: 0.146 AC: 7799 AN: 53420

Middle Eastern (MID) AF: 0.156 AC: 898 AN: 5766

European-Non Finnish (NFE) AF: 0.140 AC: 155298 AN: 1111458

Other (OTH) AF: 0.164 AC: 9930 AN: 60374

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

African (AFR) AF: 0.168 AC: 6967 AN: 41440

American (AMR) AF: 0.179 AC: 2743 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 463 AN: 3472

East Asian (EAS) AF: 0.286 AC: 1474 AN: 5156

South Asian (SAS) AF: 0.292 AC: 1405 AN: 4808

European-Finnish (FIN) AF: 0.157 AC: 1660 AN: 10570

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9448 AN: 68000

Other (OTH) AF: 0.166 AC: 350 AN: 2110

Alfa AF: 0.145 Hom.: 5867

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.9
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
Mutation Taster		=92/8	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: rs2609383; hg19: chr1-223116472; COSMIC: COSV52654796; COSMIC: COSV52654796;