1-222943132-G-T

Variant names:

• chr1-222943132-G-T
• rs2789975
• NM_001377229.1:c.309G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001350630.2(DISP1):​c.-579G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,320 control chromosomes in the GnomAD database, including 21,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2052 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19633 hom.)
• Consequence: DISP1 NM_001350630.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.42
• Publications: 21 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: SD, AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Illumina, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035224855).
• BP6: Variant 1-222943132-G-T is Benign according to our data. Variant chr1-222943132-G-T is described in ClinVar as Benign. ClinVar VariationId is 262130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350630.2. 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.309G>T	p.Glu103Asp	missense	Exon 3 of 9	NP_001364158.1	Q96F81
	DISP1	NM_001350630.2		c.-579G>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001337559.1
	DISP1	NM_001369594.1		c.309G>T	p.Glu103Asp	missense	Exon 2 of 8	NP_001356523.1	Q96F81

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISP1	ENST00000675850.1	MANE Select	c.309G>T	p.Glu103Asp	missense	Exon 3 of 9	ENSP00000502357.1	Q96F81
	DISP1	ENST00000284476.7	TSL:1	c.309G>T	p.Glu103Asp	missense	Exon 2 of 8	ENSP00000284476.6	Q96F81
	DISP1	ENST00000482856.1	TSL:1	n.456G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24669 AN: 151938 Hom.: 2040 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: 0.157

GnomAD2 exomes AF: 0.179 AC: 45022 AN: 251198 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: 228078 AN: 1461264 Hom.: 19633 Cov.: 34 AF XY: 0.159 AC XY: 115872 AN XY: 726776

African (AFR) AF: 0.164 AC: 5493 AN: 33470

American (AMR) AF: 0.198 AC: 8853 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3402 AN: 26128

East Asian (EAS) AF: 0.316 AC: 12529 AN: 39678

South Asian (SAS) AF: 0.277 AC: 23927 AN: 86248

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: 155249 AN: 1111450

Other (OTH) AF: 0.164 AC: 9928 AN: 60380

GnomAD4 genome AF: 0.162 AC: 24703 AN: 152056 Hom.: 2052 Cov.: 32 AF XY: 0.168 AC XY: 12477 AN XY: 74330

African (AFR) AF: 0.168 AC: 6967 AN: 41438

American (AMR) AF: 0.179 AC: 2741 AN: 15300

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

East Asian (EAS) AF: 0.286 AC: 1473 AN: 5158

South Asian (SAS) AF: 0.292 AC: 1404 AN: 4808

European-Finnish (FIN) AF: 0.157 AC: 1660 AN: 10568

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

European-Non Finnish (NFE) AF: 0.139 AC: 9448 AN: 67996

Other (OTH) AF: 0.165 AC: 349 AN: 2110

Alfa AF: 0.148 Hom.: 3746

Bravo AF: 0.161

TwinsUK AF: 0.150 AC: 555

ALSPAC AF: 0.134 AC: 516

ESP6500AA AF: 0.167 AC: 738

ESP6500EA AF: 0.137 AC: 1176

ExAC AF: 0.178 AC: 21671

Asia WGS AF: 0.287 AC: 994 AN: 3478

EpiCase AF: 0.142

EpiControl AF: 0.140

ClinVar

ClinVar submissions

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	0.091
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.14
Sift	Benign	0.35	T
Sift4G	Benign	0.35	T
Polyphen		0.094	B
Vest4		0.025
MutPred		0.11		Loss of glycosylation at P106 (P = 0.1882)
MPC		0.19
ClinPred		0.014	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.13
Mutation Taster		=91/9	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: rs2789975; hg19: chr1-223116474; COSMIC: COSV52654815; COSMIC: COSV52654815;