chr1-223004232-A-G

Variant names:

• chr1-223004232-A-G
• rs2609355
• NM_001377229.1:c.2835A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001377229.1(DISP1):​c.2835A>G​(p.Lys945Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,613,742 control chromosomes in the GnomAD database, including 71,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5581 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65837 hom.)
• Consequence: DISP1 NM_001377229.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.589
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-223004232-A-G is Benign according to our data. Variant chr1-223004232-A-G is described in ClinVar as Benign. ClinVar VariationId is 262128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.589 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.294 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.2835A>G	p.Lys945Lys	synonymous	Exon 9 of 9	NP_001364158.1	Q96F81
	DISP1	NM_001369594.1		c.2835A>G	p.Lys945Lys	synonymous	Exon 8 of 8	NP_001356523.1	Q96F81
	DISP1	NM_001377228.1		c.2835A>G	p.Lys945Lys	synonymous	Exon 8 of 8	NP_001364157.1	Q96F81

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DISP1	ENST00000675850.1	MANE Select	c.2835A>G	p.Lys945Lys	synonymous	Exon 9 of 9	ENSP00000502357.1	Q96F81
	DISP1	ENST00000284476.7	TSL:1	c.2835A>G	p.Lys945Lys	synonymous	Exon 8 of 8	ENSP00000284476.6	Q96F81
	DISP1	ENST00000900747.1		c.2862A>G	p.Lys954Lys	synonymous	Exon 8 of 8	ENSP00000570806.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40348 AN: 151902 Hom.: 5579 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.290 AC: 72642 AN: 250874 AF XY: 0.294

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.298 AC: 435005 AN: 1461722 Hom.: 65837 Cov.: 68 AF XY: 0.298 AC XY: 216858 AN XY: 727136

African (AFR) AF: 0.176 AC: 5898 AN: 33478

American (AMR) AF: 0.295 AC: 13209 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 8141 AN: 26136

East Asian (EAS) AF: 0.222 AC: 8811 AN: 39698

South Asian (SAS) AF: 0.314 AC: 27043 AN: 86252

European-Finnish (FIN) AF: 0.310 AC: 16562 AN: 53390

Middle Eastern (MID) AF: 0.275 AC: 1585 AN: 5768

European-Non Finnish (NFE) AF: 0.302 AC: 336323 AN: 1111912

Other (OTH) AF: 0.289 AC: 17433 AN: 60384

GnomAD4 genome AF: 0.266 AC: 40362 AN: 152020 Hom.: 5581 Cov.: 32 AF XY: 0.267 AC XY: 19804 AN XY: 74288

African (AFR) AF: 0.184 AC: 7625 AN: 41478

American (AMR) AF: 0.282 AC: 4318 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1059 AN: 3472

East Asian (EAS) AF: 0.223 AC: 1146 AN: 5134

South Asian (SAS) AF: 0.297 AC: 1429 AN: 4806

European-Finnish (FIN) AF: 0.328 AC: 3457 AN: 10554

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20248 AN: 67964

Other (OTH) AF: 0.280 AC: 591 AN: 2112

Alfa AF: 0.283 Hom.: 3468

Bravo AF: 0.260

Asia WGS AF: 0.249 AC: 868 AN: 3478

EpiCase AF: 0.298

EpiControl AF: 0.305

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
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.51
PhyloP100		-0.59
Mutation Taster		=97/3	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: rs2609355; hg19: chr1-223177574; COSMIC: COSV52659190;