rs9441940

Variant names:

• chr1-223005136-G-A
• rs9441940
• NM_001377229.1:c.3739G>A

Your query was ambiguous. Multiple possible variants found:

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

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.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. 14/21 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. 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:4
• Conservation: PhyloP100: -3.77
• Publications: 14 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=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 VariationId 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 rank	MANE	Protein	UniProt
DISP1	NM_001377229.1	c.3739G>A	p.Ala1247Thr	missense_variant	Exon 9 of 9	ENST00000675850.1	NP_001364158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISP1	ENST00000675850.1	c.3739G>A	p.Ala1247Thr	missense_variant	Exon 9 of 9		NM_001377229.1	ENSP00000502357.1

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

GnomAD2 exomes AF: 0.127 AC: 31847 AN: 251056 AF XY: 0.131

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 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

African (AFR) AF: 0.0357 AC: 1195 AN: 33480

American (AMR) AF: 0.0780 AC: 3488 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3809 AN: 26136

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39700

South Asian (SAS) AF: 0.0977 AC: 8430 AN: 86258

European-Finnish (FIN) AF: 0.165 AC: 8808 AN: 53398

Middle Eastern (MID) AF: 0.150 AC: 867 AN: 5768

European-Non Finnish (NFE) AF: 0.182 AC: 201920 AN: 1112006

Other (OTH) AF: 0.147 AC: 8871 AN: 60394

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

African (AFR) AF: 0.0397 AC: 1648 AN: 41546

American (AMR) AF: 0.104 AC: 1595 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 505 AN: 3468

East Asian (EAS) AF: 0.000968 AC: 5 AN: 5166

South Asian (SAS) AF: 0.0886 AC: 428 AN: 4828

European-Finnish (FIN) AF: 0.163 AC: 1728 AN: 10586

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12362 AN: 67988

Other (OTH) AF: 0.115 AC: 243 AN: 2112

Alfa AF: 0.149 Hom.: 3870

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		-3.8
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
Mutation Taster		=100/0	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: rs9441940; hg19: chr1-223178478; COSMIC: COSV52656020;